ADAMTS4在急性冠状动脉综合征中的诊断价值及其诱导动脉粥样硬化斑块不稳定机制的研究
|
摘要
心血管疾病已成为影响人类健康的头号杀手,据统计,每年全球近数千万人死于急性心血管事件(ACS和／或心脏性猝死)。而且大部分人没有前驱症状,现有的诊断技术难以在心血管事件前发现受害者。易损斑块的破裂、血小板聚集、血栓形成造成冠脉闭塞是ACS的发病机制已成为共识。其中动脉粥样易损斑块的破裂又视为ACS发生中最重要的始动环节。纤维帽中的细胞外基质的大量降解是斑块破裂的主要分子机制。如何在急性心血管事件发生前及早和准确地识别出易损患者并进行积极有效的干预已成为迫切的问题。
炎性标志物被越来越多地应用于ACS的病情监测,对预测易损斑块的破裂具有很高的临床价值。血清学标志物相对于其它检测手段,除了反应高危斑块外,还能够体现冠状动脉疾病的总的负荷,另外具有非侵入性,能够普遍推广,以及具有好的预测价值的特点。因此,寻找一个敏感性和特异性高的生物学标志物是我们的研究方向。
MMP-2和MMP-9是目前发现的重要的ACS的炎性标记物。MMPs产生于动脉粥样硬化斑块的脂质核心,与巨噬泡沫细胞共同存在,并能在外周血中检测到。MMPs通过降解纤维帽中的胶原和基质,使纤维帽逐渐变薄,易于破裂。
ADAMTSs是最近发现的一个新的金属蛋白酶家族成员,其分子结构及蛋白水解作用类似于MMPs。两者都含有锌依赖的内肽酶,参与ECM的蛋白水解作用。不同于MMPs, ADAMTSs还有去整合素结构域和血小板反应素结构域。
RT-PCR显示ADAMTS-4 mRNA在单核细胞里被诱导表达。在单核细胞分化为巨噬细胞过程中,ADAMTS-4 mRNA的表达升高20-30倍。另外,ADAMTS-4 mRNA表达也随着小鼠的动脉粥样硬化的进展而上调。
最新的研究发现ADAMTS-4在人的动脉粥样硬化颈动脉斑块和冠状动脉不稳定斑块的富含巨噬细胞的部位里高表达。然而,其在非动脉粥样硬化动脉里表达非常低。粥样斑块中存在丰富的巨噬细胞。斑块的纤维帽中侵入的巨噬细胞越多,斑块就越脆弱,这与巨噬细胞分泌蛋白水解酶降解ECM导致纤维帽变薄有关。由此我们推断,不稳定斑块的巨噬细胞丰富的区域里有ADAMTS4高表达,其作用也有可能类似于MMPs,通过降解ECM导致纤维帽变薄,进而诱导斑块的破裂。
ECM维持斑块结构完整性。纤维帽越薄,周向应力峰值越高,斑块越易于破裂。ECM的成分包括胶原,蛋白多聚糖(versican, biglycan, and decorin),弹性蛋白,层粘连蛋白,纤维结合素,巢蛋白。Versican是一个高分子量硫酸软骨素蛋白多聚糖,是正常血管的成分之一,在脂质核心和纤维区域连接处维持斑块的结构完整性。Versican有4个异构体(V0,V1,V2,和V3),V0,V1和V2拼接变异反映在粘多糖(GAG) (GAG-α和GAG-β)结构域的数目差异。V3缺乏(GAG-α和GAG)。它们共同分享其余的结构域包括氨基酸末端球结构域(G1)和羧基末端G3结构域以及硫酸软骨素(CS)侧链。血管壁里的versican主要是V0和V1,主要位于动脉的内膜和内膜下中层。在质脂条纹期和纤维斑块期,Versican和胶原含量较多。在高危斑块薄的纤维帽里,versican成分明显减少。因此,versican的结构瓦解可能导致纤维帽的不稳定和破裂。另外versican也在血栓形成,脂质代谢,和血管平滑肌细胞增殖和迁移中发挥着重要的作用。
ADAMTS4能够降解ECM成分aggrecan和versican,关节炎患者的关节腔滑液里存在着aggrecan的降解片段,表明ADAMTS4通过降解aggrecan导致关节软骨毁坏引发类风湿和骨关节炎。以此类推,ADAMTS4也可能通过酶切血管壁里的versican和／或aggrecan引起动脉粥样硬化。
ADAMTS-4在Glu441-Ala442／Glu1428-Ala1429位点酶切V1/V0 versican,免疫组化分析显示人的动脉粥样硬化斑块和腹部动脉瘤里有酶切产物,且在正常人的动脉抽提物中也发现了其蛋白水解产物。
最近研究表明versican的酶切片段与血管的生理和病理都存在密切的关系。
G3片段能提高内皮细胞的迁移性,促进内皮细胞分泌血管内皮生长因子,对SMCs产生趋化性。另外,G3片段通过结合P选择素糖蛋白配体-1,诱导白细胞募集到炎症部位,白细胞聚集又能加剧血栓的形成。
凭借多聚阴离子的特性,versican的硫酸软骨素链(CS)与血小板上的CD44,L-选择素,P-选择素配体结合。促进血栓的形成。
除了ECM的蛋白水解,细胞黏附也是动脉粥样硬化的中心环节。去整合素结构域能够与整合素分子相互作用,调节细胞-细胞,细胞-基质黏附作用。进而促进动脉粥样硬化。
TSP-Ⅰ结构域能与基质大分子结合。ADAMTS4的TSP-1结构域对于底物的识别和酶切是至关重要的。
基于上述事实,ADAMTS4在高危斑块里高表达；Versican是ADAMTS4的作用底物。我们提出假设ADAMTS4通过降解细胞外基质versican导致斑块破裂。另外,versican的降解片段也参与血管的病理改变；金属蛋白结构域,去整合素结构域和血细胞板反应素结构域共同存在,不同的结构域具有独立和互补作用。我们推测在动脉粥样硬化的进展中ADAMTS4比MMPs作用更强大,有希望成为反映动脉粥样硬化斑块不稳定的新的炎性标志物。
类似于MMPs,ADAMTSs能被组织金属蛋白酶抑制因子(TIMPs)抑制。ADAMTS4的羧基末端结构域参与结合TIMPs,TIMP-3是ADAMTS4强大的抑制剂。因此我们提出ADAMTS4／TIMP3的比值失调,导致versican的合成和降解失调也是斑块不稳定的原因。
血管平滑肌细胞(VSMC)向内膜增殖和迁移是动脉粥样硬化斑块形成、高血压、血管再狭窄等疾病的共同发病基础之一,在动脉粥样硬化早期,来自中层的VSMCs能够迁移到内膜,内膜增厚管腔呈现出收缩性狭窄,血流限制,表现为稳定性心绞痛。尽管其始的触发这些时间的原因不清楚,但比较认可的原因是：VSMCs释放的蛋白酶降解内膜里的基质蛋白,尤其蛋白多聚糖的主要成分versican,导致内膜容易被VSMCs入侵。已经有报导ADAMTSs家族的ADAMTS1与VSMCs迁移增殖,血管重塑有关。ADAMTS4是否也具有上述作用是未知数。
本研究旨在探讨ADAMT4能否作为临床上检测易损斑块的炎性标志物,并为其导致斑块不稳定的机制提供依据。我们推测ADAMTS-4通过两条途径促进动脉粥样硬化作用：在病变的进展中通过调节动脉平滑肌细胞迁移和发挥作用,也通过影响纤维帽的强度影响斑块的稳定。本学位论文的主要研究内容及实验结果如下：
一、稳定心绞痛和急性冠状动脉综合征患者外周血ADAMTS4抗原水平的变化
自2008年6月-2009年5月入选了132个患者和40个健康对照者。其中包括25个SAP,32个UAP,35个NSTEMI和40个STEMI,在发病3h-9h内到达我们中心。有感染、肿瘤、肝病或肾病的患者均排除。患者及对照组在入院即刻,以及冠脉造影和药物应用之前从肘静脉抽血。接受药物治疗的ACS患者在入院后的第1,2,3,5和7天连续采集血样。ADAMTS4和hs-CRP用EIASA试剂盒检测,TnT采用第三代电化学发光免疫测定法检测。
病例组的血浆ADAMTS4水平(99.2(65.8；149.2)ng／mL)明显高于对照组(51.2(38.1:64.8)ng／mL)(P<0.001).SAP组(63.1(45.2-90.3)ng／mL)；UAP组(87.5(59.4-135.6)ng／mL)；NSTEMI(113.6(68.5-160.2)ng／mL)；STEMI (127.3(76.8-220.2)ng／mL),随着病情的进展,ADAMTS4抗原水平进行性升高(P<0.001).ADAMTS4的ROC曲线下面积是0.753(95％CI 0.654-0.851:P=0.000),hs-CRP的ROC曲线下面积是0.665(95％CI 0.559-0.772;P=0.010);两者之间存在显著差异(P<0.001)。在不同类型的ACS中ADAMTS4释放曲线有明显的差异。在UAP药物治疗组,ADAMTS4在入院第2天明显提高。NSTEMI药物治疗组和STEMI药物治疗组在入院第3天达到高峰。ACS患者hs-CRP和ADAMTS4之间存在相关性(r0.719,P=0.02:r=0.660,p=0.01:r=0.888,p=0.000)；ADAMTS4最高值与hsCRP最高值之间也存在相关(r=0.700,P=0.03:r=0.632,p=0.02:r=0.769,p=0.03)。然而,在SAP患者中,没有明显的相关性(r=0.316,p=0.124)。在ACS患者中,ADAMTS4和TnT没有明显的相关性。
外周血浆ADAMTS4抗原水平可以作为斑块不稳定的标志物。
二、ADAMTS4在ACS患者外周血单个核细胞中的mRNA表达及其与复杂冠状动脉粥样硬化病变相关性的研究
2008年1月-2009年2月入选了150受试者。包括50个UAP患者,30个AMI患者,40个SAP患者,30个正常对照。所有患者都接受冠状动脉造影。采用TRIzol从单个核细胞里抽提总RNA。用RT-PCR方法分析单核细胞的ADAMTS4mRNA表达。狭窄的冠状动脉病变形态学分析参照Ambrose分类法,分为简单和复杂病变。冠状动脉狭窄的严重程度用Gensini Score (GS)方法评估。
病例组ADAMTS4 mRNA水平明显高于对照组(2.014±1.15 vs 1.201±0.402)(P ACS患者外周血单个核细胞里ADAMTS4 mRNA表达提高,与复杂的冠状动脉病变存在正向关,与狭窄的严重程度无明显相关性,因此ADAMTS4是不稳定斑块的有效的标志物。
三、动脉粥样硬化进展过程中ADAMTS4, TIMP3, versican基因表达的动态改变
选择9周龄的遗传背景C57BL／6的雄性apoE-／-小鼠,给予正常饮食喂养50周。小鼠分别在10周(n=8)、20周(n=6)、30周(n=7)、40周(n：5)、50周(n=5)麻醉处死。分离出主动脉,用Trizol提取RNA。采用Real-time RT-PCR方法测定ADAMTS4, TIMP3, versican的mRNA量,用betactin平衡。
结果显示versican在动脉粥样硬化早期已经出现。在20周达到峰值,然后表达逐渐降低,在50周时降到正常水平。在各个时期,小鼠主动脉中均没有aggrecan mRNA表达。ADAMTS-4 mRNA在10周龄已经存在于小鼠的动脉里。随着疾病的进展表达逐渐提高。在20周-30周ADAMTS-4 mRNA继续增高,40周-50周与10周比较ADAMTS-4 mRNA表达量提高了近3倍。TIMP3和ADAMTS4具有相似的表达模式。尽管TIMP3随着时间表达逐渐提高(P<0.001),但是ADAMTS4/TIMP3比值随着时间提高更显著。
在30周前,ADAMTS4和versican之间无相关性(r=0.308, p=0.415;r=0.412, p=0.352; r=0.589, p=0.172);在40和50周,在ADAMTS4和versican之间存在显著的相关性(r=0.688, p=0.02; r=0.712, p=0.000)。30周前,TIMP-3水平与versican不存在相关性(r=0.411, p=0.395; r=0.282, p=0.572; r=0.379, p=0.220); 40和50周,TIMP3和versican之间存在明显的相关性(r=0.603, p=0.03; r=0.694, p=0.002)。
ADAMTS4在动脉粥样硬化进展过程中表达上调,TIMP3与ADAMTS4增长不成比例,表明ECM的versican合成和降解的失平衡。在动脉粥样硬化早期,versican表达提高表明versican可能与脂质蛋白的储留有关,在后期下降归因于被ADAMTS4的蛋白水解。
四、在有破裂倾向的动脉粥样病变里,ADAMTS4与versican共表达。
选择遗传背景C57BL／6的10周龄的雄性apoE-/-小鼠。在手术前2周给予高脂高胆固醇饮食。用巴比妥(40-50mg／kg)腹腔注射麻醉小鼠。在其颈总动脉分叉以下用聚乙烯套环固定(2mm长度,内外径分别为：0.58mm/0.965mm),继续给予高脂高胆固醇饮食喂养20周。
颈圈放置20周,动物被处死前24小时,给予苯肾上腺素腹腔注射(8μg／kg),电击小鼠的足底,冰浴20分钟。麻醉后,右心耳摘除,左心室灌注PBS,将血管里血液冲洗干净。颈总动脉及其分支都被移除。将血管浸埋于OCT包埋剂,然而将组织投入液氮中10～20秒；使用恒温冷冻切片机,连续切片,切片厚度为5um,按照顺序编号,切好的冰冻切片,室温下自然晾干1～2h后,放入4℃丙酮固定10分钟,待干燥后封存于-20℃。相邻的片子,一张用于检测ADAMTS4蛋白表达；另一张用于versican的蛋白表达；剩余一张用于Movt's Pentachrome特殊染色。对于阴性对照组,我们以等比稀释度用preimmune血清处理切片。
抗-ADAMTS4抗体被稀释1：200,抗-versican抗体被稀释1：250。参照Vectastain ABC Elite试剂盒厂家说明。3,3’-二氨基联苯胺四盐酸盐作为发光底物。切片用Harris hematoxylin复染。我们用Pentachrome着色切片识别弹性蛋白,胶原,蛋白多聚糖沉淀区域。绿-浅绿着色提示蛋白多聚糖,该部位有ADAMTS4阳性表达。Veriscan的免疫着色证实,也存在于相同的部位。
在倾向于斑块破裂的部位,ADAMTS4表达和versican空间结构相关性提示versican被ADAMTS4降解导致斑块的不稳定。
五、ADAMTS4促进血管平滑肌细胞的迁移。
用Transwell's小室法检测VSMCs的迁移。RT-PCR被用来观察ADAMTS4 mRNA表达。RT-PCR显示迁移VSMCs的ADAMTS4 mRNA (13.1±6.5)明显高于静止期VCMCs(4.3±1.5)(p<0.01)。
ADAMTS4在体外能有效的促进VCMCs迁移。我们的研究显示ADAMTS-4可能通过调节VSMC迁移引起动脉粥样硬化。
Cardiovascular disease is the leading cause of disease and death in the developed world. Acute coronary syndromes are most frequently caused by acute disruption of an atheromatous plaque. Plaque rupture is the most frequent cause of thrombosis. The excessive degradation of the extracellular matrix scaffold has been implicated as one of the major molecular mechanisms in this process. Apparently healthy subjects at risk for major cardiovascular events (acute coronary syndrome and/or sudden cardiac death) fuels demand for detection, interventions early.
The unstable plaque are subject to excessive inflammation. Recent investigations have indicated that increases in biomarkers may provide an earlier assessment of overall patient risk and aid in identifying patients with higher risk of having an adverse event. Peripheral blood levels of biomarkers may be increased in patients with acute coronary syndrome, raising the interesting question of the possibility to develop noninvasive tests for detection of plaque vulnerability.There is growing interest in the search of a novel specific and sensitive circulating markers of vulnerable plaque.
Recent studies suggest that MMP-2 and MMP9 may be of value in recognizing patients with ACS as an important biomarkers. MMPs expressed in human atherosclerotic lesions around the lipid core; they generally colocalize with macrophages/foam cells.Focal overexpression of activated MMPs may promote destabilization and complication of atherosclerotic plaques by degrading ECM collagen of overlying cap.
ADAMTSs is a recently described family of proteinases. Structure of ADAMTS are compared with that of MMPs. The catalytic site consensus is present in ADAMTSs and MMPs, which is highly conserved Zn-dependent endopeptidases involved in proteolytic processes in the ECM. Different from MMPs,in the structure of ADAMTS,the disintegrin-like domain and TSP motif is followed
Real time RT-PCR showed that ADAMTS-4 mRNA was induced in monocytes. Expression of ADAMTS-4 mRNA were enhanced 20-30-fold during monocyte to macrophage differentiation. In addition, ADAMTS-4 expression is upregulated during the development of atherosclerosis in mice.
Because these vulnerable areas contain numerous macrophages, it is generally thought that the presence of these cells and their local release of matrix-degrading proteinases cause rupture of the plaque structure.The present work show that ADAMTS-4 were expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques. Whereas ADAMTS-4 expression was low in non-atherosclerotic aortas.We hypothesized that macrophage-derived ADAMTS4 play a role in initiating rupture of susceptible atherosclerotic lesions by degrading some structural ECM matrix component.
ECM maintains the structural integrity of plaques. In addition to collagens, proteoglycans(versican, biglycan, and decorin), elastin, laminin,fibronectin, entactin are all ECM.Thinning of the fibrous cap has been shown to increase circumferential stress on the plaque and is generally regarded as a transitional step to plaque rupture.Versican, a high molecular weight chondroitin sulfate proteoglycan, is a component of normal blood vessels. Thus, cleavage of this structural proteoglycan at the periphery of the lipid cores could conceivably lead to cap destabilization and rupture.
Collagen degradation within the fibrous cap is a critical factor in provoking rupture, the loss of versican in this region has received much attention. The degradation of versican in advanced human atheroma has been attributed to the expression of MMP7, MMP12 as well as serine protease plasminand the ADAMTSs family of metalloproteinases.
Versican is one number of matrix component that maintains the structural integrity of plaques at the junction of the lipid core and cellular fibrous regions. Four isoforms of versican (V0, V1, V2, and V3), which vary by the presence or absence of two glycosaminoglycan (GAG) binding domains named aGAG and (3GAG. All forms of versican share the remaining domains that include the amino-terminal globular domain (G1; which contains the hyaluronan-binding link modules) and the carboxy-terminal G3 domain. In the blood vessel wall, in which V0 and V1 predominantly found.
Not only do these molecules contribute to plaque burden, they also influence fundamental cellular and extracellular events associated with the pathogenesis of vascular lesions, such as thrombosis, lipid metabolism, and vascular proliferation and migration.
Consequently, ADAMTS4 possesses substrate specificity and efficiently degrades extracellular matrix components aggrecan and versican. The aggrecan products generated by this enzyme are found in synovial fluid from patients with arthritis, suggesting that ADAMTS4 may be important in diseases involving cartilage destruction. ADAMTS4 is believed to play a key role in the destruction of articular cartilage through aggrecan degradation in human arthritides such as rheumatoid arthritis and osteoarthritis and. By analogy to its action on aggrecan in arthritis, it is likely that ADAMTS4 cleaves the core protein of versican or/and aggrecan in atherosclerotic lesions remains unclear.
ADAMTS-4 has been reported to cleave either native versican or versican peptide substrates, ADAMTS-4 have been shown to cleave V1/V0 versican at the V1/V0 versican at the Glu441-Ala442/Glu1428-Ala1429 bond and the product of this cleavage was shown to be present in human atherosclerotic plaques and aneurysms by immunohistochemistry using neo-epitope antibodies. Such lower molecular weight species were also observed in extracts of normal human aorta..
Recent work that suggests that cleavage of versican into discrete fragments may occur not only as normal physiologic turnover of the vascular extracellular matrix, but also be involved in vascular pathology.
The G3 domain also increases migration of endothelial cells and the secretion of fibronectin and vascular endothelial growth factor, both of which are chemotactic for SMCs. The G3 domain has also been implicated in macrophage aggregation, as it has been shown to bind P-selectin glycoprotein ligand-1 (PSGL-1) a glycoprotein expressed on the cell surface of leukocytes, and this activity could turn out to be critically important in promoting leukocyte accumulation thrombus formation during the inflammatory phases in developing lesions of atherosclerosis.
By virtue of their polyanionic nature, the chondroitin sulfate chains attached to the aGAG and PGAG domains of versican are involved in a range of functions. Binding of versican to CD44, L selectin, and P selectin is also mediated by the chondroitin sulfate chains. That changes in CS chains can alter factor Xa-anti-thrombin-CS interactions and influence the thrombotic balance in atherosclerotic tissue.
There is accumulating evidence that disintegrin domain also displays potent proatherogenic properties. Cell adhesion and proteolytic matrix degradation are central processes in atherosclerosis. The disintegrin domain has been widely described as being able to interact with integrin molecules and therefore mediats cell-cell and cell-matrix interactions.
The TSP type I motif of thrombospondin has been implicated in binding to matrix macromolecules and cell adhesion.TSP-1 motif of ADAMTS4 is critical for substrate recognition and cleavage.
On the basis of the fact that ADAMTS4 was highly prominent at the advanced plaque lesions; versican is a high-risk substrate of ADAMTS4. Thus, it is tempting to speculate that ADAMTS4 provoke atherosclerotic plaque rupture by degrading the versican.
On the other hand,ADAMTS4 potently and thoroughly degrades versican; the discrete fragments of versican were involved in vascular pathology;the coexistence of a zinc-protease and a disintegrin domain and the thrombospondin type I motifs, therefore, the different domains composing ADAMTS4 have independent but complementary functions. We speculate that ADAMTS4 is likely a key player in atherosclerosis development.
Similar to the MMPs, the ADAMTSs can be inhibited by tissue inhibitors of metalloproteinases (TIMPs) because the C-terminal domain of ADAMTS participates in the binding of TIMPs. TIMP-3 is a potent inhibitor of ADAMTS4. So we suppose that the unbalance of circulating levels of ADAMTS4 and TIMP3 determine cap thinning, and sequently resulted in plaque stability.
Early in atherogenesis, VSMCs from the media are thought to migrate into the intima and contribute to the development of atherosclerotic lesions. Although what initially triggers these events is not known, it is thought that proteases released by VSMCs degrade the matrix proteins in the intima, particularly the main proteoglycan of the arterial intima versican, making the intima more permissive for invasion by VSMCs. It is unclear wether ADAMTS-4 may modulate VSMC migration.
Therefore, we undertook this study to:(i)assess ADAMTS4 may be of value in recognizing patients with ACS as an important biomarkers; (ii)investigat mechanisms of ADAMTS4 provoking atherosclerotic plaque rupture.The research contents and main results are as follows:
1. ADAMTS4 level in patients with stable coronary artery disease and acute coronary syndromes
A total number of 132 patients and 40 healthy subjects were involved in the study.25 patients with SAP,32 patients with UAP,35 patients with NSTEMI and 40patients with STEAMI were admitted to our institution within 3h-9h from the onset of symptom onset. Exclusion criteria were infection, tumor, liver or kidney diseases.Plasma levels of ADAMTS4 were measured in patients with stable effort angina pectoris (SAP),ACS and in controls. Venous blood was sampled upon admission before angiography and drug administration. In patients with ACS who underwent medical treatment, serial blood samples were also collected on days 1,2,3, 5 and 7 after admission. ADAMTS4 was measured using an enzyme immunoassay. Plasma ADAMTS4 level in cases (99.2(65.8; 149.2)ng/mL was significantly greater than in controls (51.2 (38.1; 64.8) ng/mL) (P<0.001). Higher levels of ADAMTS4 were found with progression of CAD from SAP (63.1 (45.2-90.3) ng/mL) to UAP (87.5(59.4-135.6)ng/mL) to NSTEMI (113.6(68.5-160.2) ng/mL) and to STEMI (127.3 (76.8-220.2) ng/mL) (P < 0.001). Elevated ADAMTS4 level was associated with ACS with an area under receiver operating characteristic (ROC) curve of 0.753 (95%CI 0.654-0.851; P< 0.001). The pattern of ADAMTS4 release observed was clearly different in various forms of ACS. In the UAP-M group, significant ADAMTS4 elevations was seen on day 2. The maximum value in both NSTEMI-M group and STEMI-M group was reached later than UAP group with a peak on day 3.
There was a weak relationship between hs-CRP and ADAMTS4 in patients with ACS (r= 0.719, P=0.02;r=0.660,p=0.01; r=0.888,p=0.000 respectively)and Maximal ADAMTS4 levels were associated with maximal hsCRP levels (r= 0.700, P=0.03;r=0.632,p=0.02; r=0.769,p=0.03).however, no significant correlation was found between ADAMTS4 and TnT in ACS patients.
Serial changes in plasma ADAMTS4 were documented in patients with ACS and may serve as a marker of plaque destabilization.
2. Elevated ADAMTS4 mRNA expression in peripheral monocytes and the correlation with the severity of coronary lesions in acute coronary syndrome patients
150 subjects were divided into unstable angina pectoris (UAP) group (n= 50), acute myocardial infarction (AMI)group (n=30)stable angina pectoris (SAP) group (n =40), and controls (n= 30). coronary angiography was performed for all these patients. Total RNA was extracted from monocytes by use of TRIzol reagent. The expression of ADAMTS4 in monocytes was analyzed by RT-PCR. Coronary stenosis was assessed morphologically according to the Ambrose classification and was classified as either simple or complex. Gensini Score (GS)was used to evaluate the severity of coronary stenosis.
ADAMTS4 mRNA level in cases was significantly greater than in controls (2.014±1.15 vs 1.201±0.402) P<0.001). Higher levels of ADAMTS4 mRNA were found in ACS group compared with SAP group (2.236±0.108 vs 1.333±0.432) (P<0.001).Correlation analysis showed that ADAMTS4 mRNA level was positively correlated with the complex coronary stenosis (r=0.58, p< 0.001). however, no significant correlation was found between ADAMTS4 mRNA level and the scores of Gensini in cases(r=0.118, P=0.201). Complex lesions were more frequent in the ACS group than in the SAP group (92%vs.13%,p<0.01).
Patients with ACS show increased ADAMTS4 mRNA expression in peripheral monocytes which has positive relationship with the severity of coronary artery lesions, hence is an effective biomarker for ACS.
3. Altered expression of ADAMTS4, TIMP3, Versican during the development of atherosclerosis in ApoE-/-mice.:results of quantitative tissue analysis using real-time RT-PCR method.
Male apoE-/-mice on a primarily C57BL/6 genetic background acquired were 9 weeks old at the time of entry into the study and develops atherosclerosis on a normal diet. Mice were euthanized at 10 (n=8),20 (n=6),30 (n=7),40 (n=5),50 (n=5) and 40 (n=5) weeks and aortas were isolated in Trizol (Invitrogen) for RNA isolation.The amounts of mRNA for ADAMTS4, TIMP3, versican were determined by real-time RT-PCR method, and normalized with.betaactin.
ADAMTS-4 mRNA was present in the mouse aortas before atherosclerotic lesions were visible (weeks 10). ADAMTS-4 mRNA was higher in mice with intermediate lesions (weeks 20 and 30) and almost 3-fold higher in late lesions (weeks 40 and 50) compared with the level in lesions (weeks 10 weeks). In contrast, aggrecan mRNA was undetectable in this model.
TIMP3 and ADAMTS4 showed similar patterns of expression with age in apoE-/-mice. Although TIMP3 showed a steady increase with time (between 10 and 50 weeks, P<0.001). Interestingly, the indices of ADAMTS4/TIMP3 still significantly increased with time,.
Before weeks30, there is no accociation between ADAMTS4 and versican (r=0.308,p=0.415; r=0.412,p=0.352; r=0.589,p=0.172); On weeks 40 and 50,there is strong accociation between ADAMTS4 and versican (r=0.688, p=0.02; r=0.712, p=0.000)
Bofore weeks 30, TIMP-3 level was not positively correlated with the versican (r=0.411, p=0.395; r=0.282, p=0.572; r=0.379, p=0.220); On weeks 40 and 50, there is siginificant association between TIMP3 and versican (r=0.603, p=0.03; r=0.694, p=0.002).
The upregulation of ADAMTS4 in development of atherosclerosis was disproportional to that of TIMP3 suggested that imbalanced degradation and synthesis of ECM versican.our study shows that the expression of versican is augmented during early atherogenesis suggesting that versican may contribute to the retention of lipoproteins at the earliest stages of murine atherosclerosis and at later stages decreacing possibly as a result of the degradation of ADAMTS4. Overall, versican accumulation reflected increased lesion development until such time as necrotic events deteriorated lesion architecture.
4. ADAMTS4 is expressed at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition
Although previous studies have confirmed the involvement of versican and ADAMTS4 in atherosclerotic disease, it is not clear whether the degration of versican is associated with plaque rupture. There is little current knowledge of the relevance of versican and ADAMTS4 in the fibrous cap of advanced plaques. We performed immunohistochemical analysis to determine whether ADAMTS4 degrade versican in rupture-phone plaques lesion.
Male apoE-/-mice were acquired were 10 weeks old at the time of entry into the study. Unless otherwise stated, the animals received a Western-type diet 2 weeks before surgery. Mice were anesthetized by subcutaneous injection of.barbitone.(0.04 mg/kg). Access to the anterior cervical triangles was gained through a sagittal anterior neck incision.
20 weeks after collar placement, the animals were anesthetized and exsanguinated by femoral artery transection. Subsequently, both carotid bifurcations and common carotid arteries were removed, these were immediately snap-frozen in liquid nitrogen after having been embedded in OCT compound (Tissue-Tek; Sakura Finetek), the specimens were stored at-20℃until further use. Transverse 5-μm cryosections were prepared in a proximal direction from the carotid bifurcation and mounted in order on a parallel series of slides.
Endogenous peroxidase activity was blocked by incubation in 0.3%H2O2 for 30 min at room temperature. Anti-ADAMTS4 antibody was diluted 1:200, and anti-versican antibody was diluted 1:250.Bound antibody was detected using a Vectastain ABC Elite kit following the manufacturer's instructions and 3,3'-diaminobenzidine tetrahydrochloride as the chromogenic substrate. Sections were counterstained with Harris hematoxylin.
We found that ADAMTS4 was prominently expressed at sites susceptible to rupture, particularly where cellular and acellular areas are juxtaposed. We stained sections with Pentachrome to identify areas of elastin, collagen, proteoglycan, and fibrin deposition. Green-to-pale green staining, indicative of proteoglycan, was consistently seen in the areas where ADAMTS4-positive were detected. Immunostaining for versican, an was present in these same areas. The close spatial correlation of ADAMTS4 expression and versican in areas potentially vulnerable to rupture suggest that plaque destabilization may result upon degradation of versican by ADAMTS4.
5. Effect of ADAMTS4 on the migration of Vascular smooth muscle cells
Investigate ADAMTS4 effect on the migration in vitro of rat primary cultured thoracic aortic vascular smooth cells(VSMCs).
Migration of VSMCs was assayed by a microchemotaxis chamber and a polycarbonate filter(Transwell's chamber)with pores of 8um in diameter. Real time polymerase chain reaction(RT-PCR)was used to detect the expression of ADAMTS4 mRNA.
RT-PCR revealed that the expression of ADAMTS4 mRNA of migrating VSMCs(13.1±6.5) was significantly higher than that of resting VCMCs(4.3±1.5) (p <0.01).
ADAMTS4 promotes the migration of VCMCs effectively in vitro.Our study showed that ADAMTS-4 may be involved in atherogenesis by modulating VSMC migration.
炎性标志物被越来越多地应用于ACS的病情监测,对预测易损斑块的破裂具有很高的临床价值。血清学标志物相对于其它检测手段,除了反应高危斑块外,还能够体现冠状动脉疾病的总的负荷,另外具有非侵入性,能够普遍推广,以及具有好的预测价值的特点。因此,寻找一个敏感性和特异性高的生物学标志物是我们的研究方向。
MMP-2和MMP-9是目前发现的重要的ACS的炎性标记物。MMPs产生于动脉粥样硬化斑块的脂质核心,与巨噬泡沫细胞共同存在,并能在外周血中检测到。MMPs通过降解纤维帽中的胶原和基质,使纤维帽逐渐变薄,易于破裂。
ADAMTSs是最近发现的一个新的金属蛋白酶家族成员,其分子结构及蛋白水解作用类似于MMPs。两者都含有锌依赖的内肽酶,参与ECM的蛋白水解作用。不同于MMPs, ADAMTSs还有去整合素结构域和血小板反应素结构域。
RT-PCR显示ADAMTS-4 mRNA在单核细胞里被诱导表达。在单核细胞分化为巨噬细胞过程中,ADAMTS-4 mRNA的表达升高20-30倍。另外,ADAMTS-4 mRNA表达也随着小鼠的动脉粥样硬化的进展而上调。
最新的研究发现ADAMTS-4在人的动脉粥样硬化颈动脉斑块和冠状动脉不稳定斑块的富含巨噬细胞的部位里高表达。然而,其在非动脉粥样硬化动脉里表达非常低。粥样斑块中存在丰富的巨噬细胞。斑块的纤维帽中侵入的巨噬细胞越多,斑块就越脆弱,这与巨噬细胞分泌蛋白水解酶降解ECM导致纤维帽变薄有关。由此我们推断,不稳定斑块的巨噬细胞丰富的区域里有ADAMTS4高表达,其作用也有可能类似于MMPs,通过降解ECM导致纤维帽变薄,进而诱导斑块的破裂。
ECM维持斑块结构完整性。纤维帽越薄,周向应力峰值越高,斑块越易于破裂。ECM的成分包括胶原,蛋白多聚糖(versican, biglycan, and decorin),弹性蛋白,层粘连蛋白,纤维结合素,巢蛋白。Versican是一个高分子量硫酸软骨素蛋白多聚糖,是正常血管的成分之一,在脂质核心和纤维区域连接处维持斑块的结构完整性。Versican有4个异构体(V0,V1,V2,和V3),V0,V1和V2拼接变异反映在粘多糖(GAG) (GAG-α和GAG-β)结构域的数目差异。V3缺乏(GAG-α和GAG)。它们共同分享其余的结构域包括氨基酸末端球结构域(G1)和羧基末端G3结构域以及硫酸软骨素(CS)侧链。血管壁里的versican主要是V0和V1,主要位于动脉的内膜和内膜下中层。在质脂条纹期和纤维斑块期,Versican和胶原含量较多。在高危斑块薄的纤维帽里,versican成分明显减少。因此,versican的结构瓦解可能导致纤维帽的不稳定和破裂。另外versican也在血栓形成,脂质代谢,和血管平滑肌细胞增殖和迁移中发挥着重要的作用。
ADAMTS4能够降解ECM成分aggrecan和versican,关节炎患者的关节腔滑液里存在着aggrecan的降解片段,表明ADAMTS4通过降解aggrecan导致关节软骨毁坏引发类风湿和骨关节炎。以此类推,ADAMTS4也可能通过酶切血管壁里的versican和／或aggrecan引起动脉粥样硬化。
ADAMTS-4在Glu441-Ala442／Glu1428-Ala1429位点酶切V1/V0 versican,免疫组化分析显示人的动脉粥样硬化斑块和腹部动脉瘤里有酶切产物,且在正常人的动脉抽提物中也发现了其蛋白水解产物。
最近研究表明versican的酶切片段与血管的生理和病理都存在密切的关系。
G3片段能提高内皮细胞的迁移性,促进内皮细胞分泌血管内皮生长因子,对SMCs产生趋化性。另外,G3片段通过结合P选择素糖蛋白配体-1,诱导白细胞募集到炎症部位,白细胞聚集又能加剧血栓的形成。
凭借多聚阴离子的特性,versican的硫酸软骨素链(CS)与血小板上的CD44,L-选择素,P-选择素配体结合。促进血栓的形成。
除了ECM的蛋白水解,细胞黏附也是动脉粥样硬化的中心环节。去整合素结构域能够与整合素分子相互作用,调节细胞-细胞,细胞-基质黏附作用。进而促进动脉粥样硬化。
TSP-Ⅰ结构域能与基质大分子结合。ADAMTS4的TSP-1结构域对于底物的识别和酶切是至关重要的。
基于上述事实,ADAMTS4在高危斑块里高表达；Versican是ADAMTS4的作用底物。我们提出假设ADAMTS4通过降解细胞外基质versican导致斑块破裂。另外,versican的降解片段也参与血管的病理改变；金属蛋白结构域,去整合素结构域和血细胞板反应素结构域共同存在,不同的结构域具有独立和互补作用。我们推测在动脉粥样硬化的进展中ADAMTS4比MMPs作用更强大,有希望成为反映动脉粥样硬化斑块不稳定的新的炎性标志物。
类似于MMPs,ADAMTSs能被组织金属蛋白酶抑制因子(TIMPs)抑制。ADAMTS4的羧基末端结构域参与结合TIMPs,TIMP-3是ADAMTS4强大的抑制剂。因此我们提出ADAMTS4／TIMP3的比值失调,导致versican的合成和降解失调也是斑块不稳定的原因。
血管平滑肌细胞(VSMC)向内膜增殖和迁移是动脉粥样硬化斑块形成、高血压、血管再狭窄等疾病的共同发病基础之一,在动脉粥样硬化早期,来自中层的VSMCs能够迁移到内膜,内膜增厚管腔呈现出收缩性狭窄,血流限制,表现为稳定性心绞痛。尽管其始的触发这些时间的原因不清楚,但比较认可的原因是：VSMCs释放的蛋白酶降解内膜里的基质蛋白,尤其蛋白多聚糖的主要成分versican,导致内膜容易被VSMCs入侵。已经有报导ADAMTSs家族的ADAMTS1与VSMCs迁移增殖,血管重塑有关。ADAMTS4是否也具有上述作用是未知数。
本研究旨在探讨ADAMT4能否作为临床上检测易损斑块的炎性标志物,并为其导致斑块不稳定的机制提供依据。我们推测ADAMTS-4通过两条途径促进动脉粥样硬化作用：在病变的进展中通过调节动脉平滑肌细胞迁移和发挥作用,也通过影响纤维帽的强度影响斑块的稳定。本学位论文的主要研究内容及实验结果如下：
一、稳定心绞痛和急性冠状动脉综合征患者外周血ADAMTS4抗原水平的变化
自2008年6月-2009年5月入选了132个患者和40个健康对照者。其中包括25个SAP,32个UAP,35个NSTEMI和40个STEMI,在发病3h-9h内到达我们中心。有感染、肿瘤、肝病或肾病的患者均排除。患者及对照组在入院即刻,以及冠脉造影和药物应用之前从肘静脉抽血。接受药物治疗的ACS患者在入院后的第1,2,3,5和7天连续采集血样。ADAMTS4和hs-CRP用EIASA试剂盒检测,TnT采用第三代电化学发光免疫测定法检测。
病例组的血浆ADAMTS4水平(99.2(65.8；149.2)ng／mL)明显高于对照组(51.2(38.1:64.8)ng／mL)(P<0.001).SAP组(63.1(45.2-90.3)ng／mL)；UAP组(87.5(59.4-135.6)ng／mL)；NSTEMI(113.6(68.5-160.2)ng／mL)；STEMI (127.3(76.8-220.2)ng／mL),随着病情的进展,ADAMTS4抗原水平进行性升高(P<0.001).ADAMTS4的ROC曲线下面积是0.753(95％CI 0.654-0.851:P=0.000),hs-CRP的ROC曲线下面积是0.665(95％CI 0.559-0.772;P=0.010);两者之间存在显著差异(P<0.001)。在不同类型的ACS中ADAMTS4释放曲线有明显的差异。在UAP药物治疗组,ADAMTS4在入院第2天明显提高。NSTEMI药物治疗组和STEMI药物治疗组在入院第3天达到高峰。ACS患者hs-CRP和ADAMTS4之间存在相关性(r0.719,P=0.02:r=0.660,p=0.01:r=0.888,p=0.000)；ADAMTS4最高值与hsCRP最高值之间也存在相关(r=0.700,P=0.03:r=0.632,p=0.02:r=0.769,p=0.03)。然而,在SAP患者中,没有明显的相关性(r=0.316,p=0.124)。在ACS患者中,ADAMTS4和TnT没有明显的相关性。
外周血浆ADAMTS4抗原水平可以作为斑块不稳定的标志物。
二、ADAMTS4在ACS患者外周血单个核细胞中的mRNA表达及其与复杂冠状动脉粥样硬化病变相关性的研究
2008年1月-2009年2月入选了150受试者。包括50个UAP患者,30个AMI患者,40个SAP患者,30个正常对照。所有患者都接受冠状动脉造影。采用TRIzol从单个核细胞里抽提总RNA。用RT-PCR方法分析单核细胞的ADAMTS4mRNA表达。狭窄的冠状动脉病变形态学分析参照Ambrose分类法,分为简单和复杂病变。冠状动脉狭窄的严重程度用Gensini Score (GS)方法评估。
病例组ADAMTS4 mRNA水平明显高于对照组(2.014±1.15 vs 1.201±0.402)(P
三、动脉粥样硬化进展过程中ADAMTS4, TIMP3, versican基因表达的动态改变
选择9周龄的遗传背景C57BL／6的雄性apoE-／-小鼠,给予正常饮食喂养50周。小鼠分别在10周(n=8)、20周(n=6)、30周(n=7)、40周(n：5)、50周(n=5)麻醉处死。分离出主动脉,用Trizol提取RNA。采用Real-time RT-PCR方法测定ADAMTS4, TIMP3, versican的mRNA量,用betactin平衡。
结果显示versican在动脉粥样硬化早期已经出现。在20周达到峰值,然后表达逐渐降低,在50周时降到正常水平。在各个时期,小鼠主动脉中均没有aggrecan mRNA表达。ADAMTS-4 mRNA在10周龄已经存在于小鼠的动脉里。随着疾病的进展表达逐渐提高。在20周-30周ADAMTS-4 mRNA继续增高,40周-50周与10周比较ADAMTS-4 mRNA表达量提高了近3倍。TIMP3和ADAMTS4具有相似的表达模式。尽管TIMP3随着时间表达逐渐提高(P<0.001),但是ADAMTS4/TIMP3比值随着时间提高更显著。
在30周前,ADAMTS4和versican之间无相关性(r=0.308, p=0.415;r=0.412, p=0.352; r=0.589, p=0.172);在40和50周,在ADAMTS4和versican之间存在显著的相关性(r=0.688, p=0.02; r=0.712, p=0.000)。30周前,TIMP-3水平与versican不存在相关性(r=0.411, p=0.395; r=0.282, p=0.572; r=0.379, p=0.220); 40和50周,TIMP3和versican之间存在明显的相关性(r=0.603, p=0.03; r=0.694, p=0.002)。
ADAMTS4在动脉粥样硬化进展过程中表达上调,TIMP3与ADAMTS4增长不成比例,表明ECM的versican合成和降解的失平衡。在动脉粥样硬化早期,versican表达提高表明versican可能与脂质蛋白的储留有关,在后期下降归因于被ADAMTS4的蛋白水解。
四、在有破裂倾向的动脉粥样病变里,ADAMTS4与versican共表达。
选择遗传背景C57BL／6的10周龄的雄性apoE-/-小鼠。在手术前2周给予高脂高胆固醇饮食。用巴比妥(40-50mg／kg)腹腔注射麻醉小鼠。在其颈总动脉分叉以下用聚乙烯套环固定(2mm长度,内外径分别为：0.58mm/0.965mm),继续给予高脂高胆固醇饮食喂养20周。
颈圈放置20周,动物被处死前24小时,给予苯肾上腺素腹腔注射(8μg／kg),电击小鼠的足底,冰浴20分钟。麻醉后,右心耳摘除,左心室灌注PBS,将血管里血液冲洗干净。颈总动脉及其分支都被移除。将血管浸埋于OCT包埋剂,然而将组织投入液氮中10～20秒；使用恒温冷冻切片机,连续切片,切片厚度为5um,按照顺序编号,切好的冰冻切片,室温下自然晾干1～2h后,放入4℃丙酮固定10分钟,待干燥后封存于-20℃。相邻的片子,一张用于检测ADAMTS4蛋白表达；另一张用于versican的蛋白表达；剩余一张用于Movt's Pentachrome特殊染色。对于阴性对照组,我们以等比稀释度用preimmune血清处理切片。
抗-ADAMTS4抗体被稀释1：200,抗-versican抗体被稀释1：250。参照Vectastain ABC Elite试剂盒厂家说明。3,3’-二氨基联苯胺四盐酸盐作为发光底物。切片用Harris hematoxylin复染。我们用Pentachrome着色切片识别弹性蛋白,胶原,蛋白多聚糖沉淀区域。绿-浅绿着色提示蛋白多聚糖,该部位有ADAMTS4阳性表达。Veriscan的免疫着色证实,也存在于相同的部位。
在倾向于斑块破裂的部位,ADAMTS4表达和versican空间结构相关性提示versican被ADAMTS4降解导致斑块的不稳定。
五、ADAMTS4促进血管平滑肌细胞的迁移。
用Transwell's小室法检测VSMCs的迁移。RT-PCR被用来观察ADAMTS4 mRNA表达。RT-PCR显示迁移VSMCs的ADAMTS4 mRNA (13.1±6.5)明显高于静止期VCMCs(4.3±1.5)(p<0.01)。
ADAMTS4在体外能有效的促进VCMCs迁移。我们的研究显示ADAMTS-4可能通过调节VSMC迁移引起动脉粥样硬化。
Cardiovascular disease is the leading cause of disease and death in the developed world. Acute coronary syndromes are most frequently caused by acute disruption of an atheromatous plaque. Plaque rupture is the most frequent cause of thrombosis. The excessive degradation of the extracellular matrix scaffold has been implicated as one of the major molecular mechanisms in this process. Apparently healthy subjects at risk for major cardiovascular events (acute coronary syndrome and/or sudden cardiac death) fuels demand for detection, interventions early.
The unstable plaque are subject to excessive inflammation. Recent investigations have indicated that increases in biomarkers may provide an earlier assessment of overall patient risk and aid in identifying patients with higher risk of having an adverse event. Peripheral blood levels of biomarkers may be increased in patients with acute coronary syndrome, raising the interesting question of the possibility to develop noninvasive tests for detection of plaque vulnerability.There is growing interest in the search of a novel specific and sensitive circulating markers of vulnerable plaque.
Recent studies suggest that MMP-2 and MMP9 may be of value in recognizing patients with ACS as an important biomarkers. MMPs expressed in human atherosclerotic lesions around the lipid core; they generally colocalize with macrophages/foam cells.Focal overexpression of activated MMPs may promote destabilization and complication of atherosclerotic plaques by degrading ECM collagen of overlying cap.
ADAMTSs is a recently described family of proteinases. Structure of ADAMTS are compared with that of MMPs. The catalytic site consensus is present in ADAMTSs and MMPs, which is highly conserved Zn-dependent endopeptidases involved in proteolytic processes in the ECM. Different from MMPs,in the structure of ADAMTS,the disintegrin-like domain and TSP motif is followed
Real time RT-PCR showed that ADAMTS-4 mRNA was induced in monocytes. Expression of ADAMTS-4 mRNA were enhanced 20-30-fold during monocyte to macrophage differentiation. In addition, ADAMTS-4 expression is upregulated during the development of atherosclerosis in mice.
Because these vulnerable areas contain numerous macrophages, it is generally thought that the presence of these cells and their local release of matrix-degrading proteinases cause rupture of the plaque structure.The present work show that ADAMTS-4 were expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques. Whereas ADAMTS-4 expression was low in non-atherosclerotic aortas.We hypothesized that macrophage-derived ADAMTS4 play a role in initiating rupture of susceptible atherosclerotic lesions by degrading some structural ECM matrix component.
ECM maintains the structural integrity of plaques. In addition to collagens, proteoglycans(versican, biglycan, and decorin), elastin, laminin,fibronectin, entactin are all ECM.Thinning of the fibrous cap has been shown to increase circumferential stress on the plaque and is generally regarded as a transitional step to plaque rupture.Versican, a high molecular weight chondroitin sulfate proteoglycan, is a component of normal blood vessels. Thus, cleavage of this structural proteoglycan at the periphery of the lipid cores could conceivably lead to cap destabilization and rupture.
Collagen degradation within the fibrous cap is a critical factor in provoking rupture, the loss of versican in this region has received much attention. The degradation of versican in advanced human atheroma has been attributed to the expression of MMP7, MMP12 as well as serine protease plasminand the ADAMTSs family of metalloproteinases.
Versican is one number of matrix component that maintains the structural integrity of plaques at the junction of the lipid core and cellular fibrous regions. Four isoforms of versican (V0, V1, V2, and V3), which vary by the presence or absence of two glycosaminoglycan (GAG) binding domains named aGAG and (3GAG. All forms of versican share the remaining domains that include the amino-terminal globular domain (G1; which contains the hyaluronan-binding link modules) and the carboxy-terminal G3 domain. In the blood vessel wall, in which V0 and V1 predominantly found.
Not only do these molecules contribute to plaque burden, they also influence fundamental cellular and extracellular events associated with the pathogenesis of vascular lesions, such as thrombosis, lipid metabolism, and vascular proliferation and migration.
Consequently, ADAMTS4 possesses substrate specificity and efficiently degrades extracellular matrix components aggrecan and versican. The aggrecan products generated by this enzyme are found in synovial fluid from patients with arthritis, suggesting that ADAMTS4 may be important in diseases involving cartilage destruction. ADAMTS4 is believed to play a key role in the destruction of articular cartilage through aggrecan degradation in human arthritides such as rheumatoid arthritis and osteoarthritis and. By analogy to its action on aggrecan in arthritis, it is likely that ADAMTS4 cleaves the core protein of versican or/and aggrecan in atherosclerotic lesions remains unclear.
ADAMTS-4 has been reported to cleave either native versican or versican peptide substrates, ADAMTS-4 have been shown to cleave V1/V0 versican at the V1/V0 versican at the Glu441-Ala442/Glu1428-Ala1429 bond and the product of this cleavage was shown to be present in human atherosclerotic plaques and aneurysms by immunohistochemistry using neo-epitope antibodies. Such lower molecular weight species were also observed in extracts of normal human aorta..
Recent work that suggests that cleavage of versican into discrete fragments may occur not only as normal physiologic turnover of the vascular extracellular matrix, but also be involved in vascular pathology.
The G3 domain also increases migration of endothelial cells and the secretion of fibronectin and vascular endothelial growth factor, both of which are chemotactic for SMCs. The G3 domain has also been implicated in macrophage aggregation, as it has been shown to bind P-selectin glycoprotein ligand-1 (PSGL-1) a glycoprotein expressed on the cell surface of leukocytes, and this activity could turn out to be critically important in promoting leukocyte accumulation thrombus formation during the inflammatory phases in developing lesions of atherosclerosis.
By virtue of their polyanionic nature, the chondroitin sulfate chains attached to the aGAG and PGAG domains of versican are involved in a range of functions. Binding of versican to CD44, L selectin, and P selectin is also mediated by the chondroitin sulfate chains. That changes in CS chains can alter factor Xa-anti-thrombin-CS interactions and influence the thrombotic balance in atherosclerotic tissue.
There is accumulating evidence that disintegrin domain also displays potent proatherogenic properties. Cell adhesion and proteolytic matrix degradation are central processes in atherosclerosis. The disintegrin domain has been widely described as being able to interact with integrin molecules and therefore mediats cell-cell and cell-matrix interactions.
The TSP type I motif of thrombospondin has been implicated in binding to matrix macromolecules and cell adhesion.TSP-1 motif of ADAMTS4 is critical for substrate recognition and cleavage.
On the basis of the fact that ADAMTS4 was highly prominent at the advanced plaque lesions; versican is a high-risk substrate of ADAMTS4. Thus, it is tempting to speculate that ADAMTS4 provoke atherosclerotic plaque rupture by degrading the versican.
On the other hand,ADAMTS4 potently and thoroughly degrades versican; the discrete fragments of versican were involved in vascular pathology;the coexistence of a zinc-protease and a disintegrin domain and the thrombospondin type I motifs, therefore, the different domains composing ADAMTS4 have independent but complementary functions. We speculate that ADAMTS4 is likely a key player in atherosclerosis development.
Similar to the MMPs, the ADAMTSs can be inhibited by tissue inhibitors of metalloproteinases (TIMPs) because the C-terminal domain of ADAMTS participates in the binding of TIMPs. TIMP-3 is a potent inhibitor of ADAMTS4. So we suppose that the unbalance of circulating levels of ADAMTS4 and TIMP3 determine cap thinning, and sequently resulted in plaque stability.
Early in atherogenesis, VSMCs from the media are thought to migrate into the intima and contribute to the development of atherosclerotic lesions. Although what initially triggers these events is not known, it is thought that proteases released by VSMCs degrade the matrix proteins in the intima, particularly the main proteoglycan of the arterial intima versican, making the intima more permissive for invasion by VSMCs. It is unclear wether ADAMTS-4 may modulate VSMC migration.
Therefore, we undertook this study to:(i)assess ADAMTS4 may be of value in recognizing patients with ACS as an important biomarkers; (ii)investigat mechanisms of ADAMTS4 provoking atherosclerotic plaque rupture.The research contents and main results are as follows:
1. ADAMTS4 level in patients with stable coronary artery disease and acute coronary syndromes
A total number of 132 patients and 40 healthy subjects were involved in the study.25 patients with SAP,32 patients with UAP,35 patients with NSTEMI and 40patients with STEAMI were admitted to our institution within 3h-9h from the onset of symptom onset. Exclusion criteria were infection, tumor, liver or kidney diseases.Plasma levels of ADAMTS4 were measured in patients with stable effort angina pectoris (SAP),ACS and in controls. Venous blood was sampled upon admission before angiography and drug administration. In patients with ACS who underwent medical treatment, serial blood samples were also collected on days 1,2,3, 5 and 7 after admission. ADAMTS4 was measured using an enzyme immunoassay. Plasma ADAMTS4 level in cases (99.2(65.8; 149.2)ng/mL was significantly greater than in controls (51.2 (38.1; 64.8) ng/mL) (P<0.001). Higher levels of ADAMTS4 were found with progression of CAD from SAP (63.1 (45.2-90.3) ng/mL) to UAP (87.5(59.4-135.6)ng/mL) to NSTEMI (113.6(68.5-160.2) ng/mL) and to STEMI (127.3 (76.8-220.2) ng/mL) (P < 0.001). Elevated ADAMTS4 level was associated with ACS with an area under receiver operating characteristic (ROC) curve of 0.753 (95%CI 0.654-0.851; P< 0.001). The pattern of ADAMTS4 release observed was clearly different in various forms of ACS. In the UAP-M group, significant ADAMTS4 elevations was seen on day 2. The maximum value in both NSTEMI-M group and STEMI-M group was reached later than UAP group with a peak on day 3.
There was a weak relationship between hs-CRP and ADAMTS4 in patients with ACS (r= 0.719, P=0.02;r=0.660,p=0.01; r=0.888,p=0.000 respectively)and Maximal ADAMTS4 levels were associated with maximal hsCRP levels (r= 0.700, P=0.03;r=0.632,p=0.02; r=0.769,p=0.03).however, no significant correlation was found between ADAMTS4 and TnT in ACS patients.
Serial changes in plasma ADAMTS4 were documented in patients with ACS and may serve as a marker of plaque destabilization.
2. Elevated ADAMTS4 mRNA expression in peripheral monocytes and the correlation with the severity of coronary lesions in acute coronary syndrome patients
150 subjects were divided into unstable angina pectoris (UAP) group (n= 50), acute myocardial infarction (AMI)group (n=30)stable angina pectoris (SAP) group (n =40), and controls (n= 30). coronary angiography was performed for all these patients. Total RNA was extracted from monocytes by use of TRIzol reagent. The expression of ADAMTS4 in monocytes was analyzed by RT-PCR. Coronary stenosis was assessed morphologically according to the Ambrose classification and was classified as either simple or complex. Gensini Score (GS)was used to evaluate the severity of coronary stenosis.
ADAMTS4 mRNA level in cases was significantly greater than in controls (2.014±1.15 vs 1.201±0.402) P<0.001). Higher levels of ADAMTS4 mRNA were found in ACS group compared with SAP group (2.236±0.108 vs 1.333±0.432) (P<0.001).Correlation analysis showed that ADAMTS4 mRNA level was positively correlated with the complex coronary stenosis (r=0.58, p< 0.001). however, no significant correlation was found between ADAMTS4 mRNA level and the scores of Gensini in cases(r=0.118, P=0.201). Complex lesions were more frequent in the ACS group than in the SAP group (92%vs.13%,p<0.01).
Patients with ACS show increased ADAMTS4 mRNA expression in peripheral monocytes which has positive relationship with the severity of coronary artery lesions, hence is an effective biomarker for ACS.
3. Altered expression of ADAMTS4, TIMP3, Versican during the development of atherosclerosis in ApoE-/-mice.:results of quantitative tissue analysis using real-time RT-PCR method.
Male apoE-/-mice on a primarily C57BL/6 genetic background acquired were 9 weeks old at the time of entry into the study and develops atherosclerosis on a normal diet. Mice were euthanized at 10 (n=8),20 (n=6),30 (n=7),40 (n=5),50 (n=5) and 40 (n=5) weeks and aortas were isolated in Trizol (Invitrogen) for RNA isolation.The amounts of mRNA for ADAMTS4, TIMP3, versican were determined by real-time RT-PCR method, and normalized with.betaactin.
ADAMTS-4 mRNA was present in the mouse aortas before atherosclerotic lesions were visible (weeks 10). ADAMTS-4 mRNA was higher in mice with intermediate lesions (weeks 20 and 30) and almost 3-fold higher in late lesions (weeks 40 and 50) compared with the level in lesions (weeks 10 weeks). In contrast, aggrecan mRNA was undetectable in this model.
TIMP3 and ADAMTS4 showed similar patterns of expression with age in apoE-/-mice. Although TIMP3 showed a steady increase with time (between 10 and 50 weeks, P<0.001). Interestingly, the indices of ADAMTS4/TIMP3 still significantly increased with time,.
Before weeks30, there is no accociation between ADAMTS4 and versican (r=0.308,p=0.415; r=0.412,p=0.352; r=0.589,p=0.172); On weeks 40 and 50,there is strong accociation between ADAMTS4 and versican (r=0.688, p=0.02; r=0.712, p=0.000)
Bofore weeks 30, TIMP-3 level was not positively correlated with the versican (r=0.411, p=0.395; r=0.282, p=0.572; r=0.379, p=0.220); On weeks 40 and 50, there is siginificant association between TIMP3 and versican (r=0.603, p=0.03; r=0.694, p=0.002).
The upregulation of ADAMTS4 in development of atherosclerosis was disproportional to that of TIMP3 suggested that imbalanced degradation and synthesis of ECM versican.our study shows that the expression of versican is augmented during early atherogenesis suggesting that versican may contribute to the retention of lipoproteins at the earliest stages of murine atherosclerosis and at later stages decreacing possibly as a result of the degradation of ADAMTS4. Overall, versican accumulation reflected increased lesion development until such time as necrotic events deteriorated lesion architecture.
4. ADAMTS4 is expressed at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition
Although previous studies have confirmed the involvement of versican and ADAMTS4 in atherosclerotic disease, it is not clear whether the degration of versican is associated with plaque rupture. There is little current knowledge of the relevance of versican and ADAMTS4 in the fibrous cap of advanced plaques. We performed immunohistochemical analysis to determine whether ADAMTS4 degrade versican in rupture-phone plaques lesion.
Male apoE-/-mice were acquired were 10 weeks old at the time of entry into the study. Unless otherwise stated, the animals received a Western-type diet 2 weeks before surgery. Mice were anesthetized by subcutaneous injection of.barbitone.(0.04 mg/kg). Access to the anterior cervical triangles was gained through a sagittal anterior neck incision.
20 weeks after collar placement, the animals were anesthetized and exsanguinated by femoral artery transection. Subsequently, both carotid bifurcations and common carotid arteries were removed, these were immediately snap-frozen in liquid nitrogen after having been embedded in OCT compound (Tissue-Tek; Sakura Finetek), the specimens were stored at-20℃until further use. Transverse 5-μm cryosections were prepared in a proximal direction from the carotid bifurcation and mounted in order on a parallel series of slides.
Endogenous peroxidase activity was blocked by incubation in 0.3%H2O2 for 30 min at room temperature. Anti-ADAMTS4 antibody was diluted 1:200, and anti-versican antibody was diluted 1:250.Bound antibody was detected using a Vectastain ABC Elite kit following the manufacturer's instructions and 3,3'-diaminobenzidine tetrahydrochloride as the chromogenic substrate. Sections were counterstained with Harris hematoxylin.
We found that ADAMTS4 was prominently expressed at sites susceptible to rupture, particularly where cellular and acellular areas are juxtaposed. We stained sections with Pentachrome to identify areas of elastin, collagen, proteoglycan, and fibrin deposition. Green-to-pale green staining, indicative of proteoglycan, was consistently seen in the areas where ADAMTS4-positive were detected. Immunostaining for versican, an was present in these same areas. The close spatial correlation of ADAMTS4 expression and versican in areas potentially vulnerable to rupture suggest that plaque destabilization may result upon degradation of versican by ADAMTS4.
5. Effect of ADAMTS4 on the migration of Vascular smooth muscle cells
Investigate ADAMTS4 effect on the migration in vitro of rat primary cultured thoracic aortic vascular smooth cells(VSMCs).
Migration of VSMCs was assayed by a microchemotaxis chamber and a polycarbonate filter(Transwell's chamber)with pores of 8um in diameter. Real time polymerase chain reaction(RT-PCR)was used to detect the expression of ADAMTS4 mRNA.
RT-PCR revealed that the expression of ADAMTS4 mRNA of migrating VSMCs(13.1±6.5) was significantly higher than that of resting VCMCs(4.3±1.5) (p <0.01).
ADAMTS4 promotes the migration of VCMCs effectively in vitro.Our study showed that ADAMTS-4 may be involved in atherogenesis by modulating VSMC migration.
引文
1. James Scott. Pathophysiology and biochemistry of cardiovascular disease. Current Opinion in Genetics & Development 2004,14:271-279
2. Raggi P, Achenbach S. Computed tomography for atherosclerosis and coronary artery disease imaging.Discov Med.2010;45:98-104.
3. Ciompi F, Pujol O, Gatta C,et al. Fusing in-vitro and in-vivo intravascular ultrasound data for plaque characterization. Int J Cardiovasc Imaging.2009 Nov 29. [Epub ahead of print]
4. de Korte CL, van der Steen AF, Cepedes El, et al.Characterization of plaque components and vulnerability with intravascular ultrasound elastography. Phys Med Biol.2000 45:1465-75.
5. Takayama T. Can an intravascular imaging modality detect really vulnerable plaque? Circ J. 2010;74(2):252-3.
6. Kubo T, Imanishi T, Kashiwagi M, et al. Multiple coronary lesion instability in patients with acute myocardial infarction as determined by optical coherence tomography. AM J Cardiol. 2010;105:318-22
7. Kilic T, Jneid H, Ural E, Oner G, Sahin T, Kozdag G, Kahraman G, Ural D. Impact of the metabolic syndrome on high-sensitivity C reactive protein levels in patients with acute coronary syndrome. Atherosclerosis.2009;207:591-6.
8. Galan A, Curos A, Valle V.Biomarkers for detection and prediction in acute coronary syndrome. Med Clin (Barc).2009 May 19. [Epub ahead of print].
9. Iversen KK, Dalsgaard M, Teisner AS, Schoos M, Teisner B, Nielsen H, Clemmensen P, Grande P. Usefulness of pregnancy-associated plasma protein A in patients with acute coronary syndrome. Am J Cardiol.2009; 1;104(11):1465-71
10. Shah VK, Shalia KK, Mashru MR, Soneji SL, Abraham A, Kudalkar KV, Vasvani JB, Sanghavi ST. Role of matrix metalloproteinases in coronary artery disease.Indian Heart J. 2009;61(1):44-50.
11..G.C. Jones and G.P. Riley, ADAMTS proteinases:a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis, Arthritis Res Ther 2005; 7: 160-169.
12. B.L. Tang, ADAMTS:a novel family of extracellular matrix proteases, Int J Biochem Cell Biol 2001; 33:33-44.
13. Bor Luen Tang-and Wanjin Hong. ADAMTS:A novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats.FEBS.1999; 445:223-225
14. Claudia Andreini, Lucia Banci, Ivano Bertini, et al. Comparative Analysis of the ADAM and ADAMTS Families J. Proteome Res.2005;4:881-888..
15. M. Kashiwagi, M. Tortorella, H. Nagase and K. et al.TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5), JBiol Chem 2001; 276: 12501-12504.
16. Nadia Al-Fakhri, Jochen Wilhelm, Meinhard Hahn. Increased Expression of Disintegrin-Metalloproteinases ADAM-15 and ADAM-9 Following Upregulation of Integrins a5b1 and avb3 in Atherosclerosis.Journal of Cellular Biochemistry.2003;89:808-823
17. Ok-Hee Jeon 1, Dongbum Kim 1, Yong-Jun Choi,et al. Novel function of human ADAM 15 disintegrin-like domain and its derivatives in platelet aggregation. Thrombosis Research.2007; 119:609—619
18. Micky Tortorella, Michael Pratta, Rui-Qin Liu et al. The Thrombospondin Motif of Aggrecanase-1 (ADAMTS-4) Is Critical for Aggrecan Substrate Recognition and Cleavage J. Biol. Chem..2000; 275:25791-25797.
19. Svetlana A. Kuznetsova, Philip Issa. Versican-thrombospondin-1 binding in vitro and colocalization in microfibrils induced by inflammation on vascular smooth muscle cells Journal of Cell Science.2006; 119:4499-4509
20. Bondeson J, Wainwright S, Hughes C, et al. Clin Exp Rheumatol. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis:a review.2008;26:139-45
21. Jennifer Westling, Amanda J. Fosang, Karena Last,et al. ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain. J. Biol. Chem..2002; 277: 6059-16066.
22. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al. ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008; 196:514-522.
23. Celik T, Iyisoy A, Kardesoglu E, Bugan B, Isik E. Matrix metalloproteinases in acute coronary syndromes:a new therapeutic target. Int J Cardiol.2009 May 29;134(3):402-4
24. Merrilees MJ, Beaumont B, Scott LJ. Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency. Coron Artery Dis.2001; 12:7-16.
25. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2001; 21:1053-1058
26. Olin AI, Morgelin M, Sasaki T, Timpl R, Heinegard D, Asperg A. The proteoglycan aggrecan and versican form networks with fibulin-2 through their lectin domain binding. JBiol Chem. 2001; 276:1253-1261
27. Theocharis AD, Tsolakis I, Hjerpe A, Karamanos NK. Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V0. Atherosclerosis.2001; 154:367-376.
28. J.D. Sandy, J. Westling and R.D. Kenagy Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, JBiol Chem.2001; 276:13372-13378.
29. Yaou Zhang, Liu Cao, Bing L. Yang, and Burton B. Yang.The G3 Domain of Versican Enhances Cell Proliferation via Epidermial Growth Factor-like Motifs. J Biol Chem. 1998;273:21342-21351.
30. Peng-Sheng Zheng, Dana Vais, David LaPierre,et al. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation.Journal/of Cell Science.2004;117: 5887-5895
31. Gakuji Hashimoto, Takanori Aoki, Hiroyuki Nakamura,et al. Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1,2,3 and 4) FEBS.2001;494:192-195
32. Ann-Cathrine Jonsson-Rylander; Tina Nilsson; Regina Fritsche-Danielson, et al. Role of ADAMTS-1 in Atherosclerosis Remodeling of Carotid Artery, Immunohistochemistry, and Proteolysis of Versican Arteriosclerosis, Thrombosis, and Vascular Biology.2005;25:180.-185
1. Bor Luen Tang.ADAMTS:a novel family of extracellular matrix proteases.The International Journal of Biochemistry & Cell Biology.2001;3:33-44.
2. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards.The ADAMTS metalloproteinases, Biochem J 2005;386:15-27.
3. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al.ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008;196:514-522.
4. Richard D. Kenagy, Anna H. Plaas and Thomas N. Wight.Versican Degradation and Vascular Disease.Trends in Cardiovascular Medicine.2006; 16:209-215
5. J.D. Sandy, J. Westling and R.D. Kenagy Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem.2001; 276:13372-13378.
6. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2005; 21:1053-1058
7. Joanna R. Worley, Mark D. Baugh, David A. Hughes, Dylan R. Edwards, Aileen Hogan, Mike J. Sampson, Jelena GavrilovicMetalloproteinase Expression in PMA-stimulatedTHP-1 cells effects of peroxisome proliferator-activated receptor-THP-1-γ (PPARγ) agonists and 9-cis-retinoic acid J. Biol. Chem. 2003;51:51340-51346
8. Yaou Zhang, Liu Cao, Bing L. Yang, and Burton B. Yang.The G3 Domain of Versican Enhances Cell Proliferation via Epidermial Growth Factor-like Motifs. J Biol Chem.1998;273:21342-21351.
9. Peng-Sheng Zheng, Dana Vais, David LaPierre,et al. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation.Journal of Cell Science.2004;117:5887-5895
10. eLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves:a nonparametric approach. Biometrics.2006;.44:837-45.
11. hah VK, Shalia KK, Mashru MR, Soneji SL, Abraham A, Kudalkar KV, Vasvani JB, Sanghavi ST. Role of matrix metalloproteinases in coronary artery disease.Indian Heart J.2009;61(1):44-50.
12. lin AI, Morgelin M, Sasaki T, Timpl R, Heinegard D, Asperg A. The proteoglycan aggrecan and versican form networks with fibulin-2 through their lectin domain binding. J Biol Chem.2001; 276:1253-1261
13. heocharis AD, Tsolakis I, Hjerpe A, Karamanos NK. Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V0. Atherosclerosis.2001; 154:367-376.
14. errilees MJ, Beaumont B, Scott LJ. Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries: correlation to patency. Cor on Artery Dis.2001; 12:7-16.
15. akala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2001; 21:1053-1058
16. ennifer Westling, Amanda J. Fosang, Karena Last,et al. ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain. J. Biol. Chem..2002; 277:6059-16066.
17. Zorina S. Galis, Jaikirshan J. Khatri.Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly Circulation Research.2004; 90:251.
18..K. Reiss, A. Ludwig, P. Saftig.Breaking up the tie:disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacol. Ther.2006; 111:985-1006
19. vanko, S. P., Raines, E. W., Ross, R., Gold, L. I., and Wight, T. N. Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am. J. Pathol.1998; 152:533-546.
20. irmani R, Burke AP, Farb A.(1999) Plaque rupture and plaque erosion. Thromb Haemost.1999; 82:1-3.
21. Zorina S. Galis, Jaikirshan J. Khatri. Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly.. Circ. Res. 2002; 90:251-262
1. Lijnen, H. R., J. Silence, G. Lemmens, L. Frederix, and D. Collen. Regulation of gelatinase activity in mice with targeted inactivation of components of the plasminogen/plasmin system. Thromb. Haemost.1998;79:1171-1176.
2. Galis, Z. S., G. K. Sukhova, R. Kranzhofer, S. Clark, and P. Libby. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc. Natl. Acad. Sci. USA.1995;92:402—406.
3..Zorina S. Galis, Jaikirshan J. Khatri.Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly. Circulation Research.2002;90:251.
4. Joanna R. Worley, Mark D. Baugh, David A. Hughes, Dylan R. Edwards, Aileen Hogan, Mike J. Sampson, Jelena Gavrilovic. Metalloproteinase Expression in PMA-stimulated THP-1 Cells effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonists and 9-cis-retinoic acid. J. Biol. Chem.2003;51: 51340-51346.
5. Goldstein JA, Demetriou D, Grines CL, et al.Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med.2000;28:915-922.
6. Kaski JC, Chester MR, Chen L, Katritsis D.Rapid angiographic progression of coronary artery disease in patients with angina pectoris:the role of complex stenosis morphology. Circulation.2005;92:2058-2065.
7. Sullivan DR, Marwick TH, Freedman SB. A new method of scoring coronary angiograms to reflect extent of coronary atherosclerosis and improve correlation with major risk factors. Am Heart J 1990;119:1262-7.
8. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al.ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008;196:514-522.
9. Richard D. Kenagy, Anna H. Plaas and Thomas N. Wight. Versican Degradation and Vascular Disease.Trends in Cardiovascular Medicine.2006; 16:209-215
10. R. Worley, M.D. Baugh and D.A. Hughes et al., Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid, JBiol Chem. 2003;278:51340-51346.
11. Uma Singh, Sridevi Devaraj and Ishwarlal Jialal C-Reactive Protein Stimulates Myeloperoxidase Release from Polymorphonuclear Cells and Monocytes: Implications for Acute Coronary Syndromes.. Clinical Chemistry 2009;55: 361-364.
12. Divies MJ. Stability and instability:two faces of coronaryatherosclerosis.Circulation.2002;94:2013-20.
13. Schroeder AP, Falk E.Vulnerable and dangerous coronary plaques. Atherosclerosis.2006; 118:S 141-9
14. Wilson RF, Holida MD, White CW. Quantitative angiographic morphology of coronary stenoses leading to myocardial infarction or unstable angina. Circulation.1999; 73:286-93.
15. Katritsis D, Korovesis S, Giazitzoglou E, et al. C-Reactive protein concentrations and angiographic characteristics of coronary lesions.Clin Chem 2005;47(5):882-
1. Merrilees MJ, Beaumont B, Scott LJ. Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency. Coron Artery Dis.2001; 12:7-16.
2. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2003; 21:1053-1058
3. Wight TN. The vascular extracellular matrix. In:Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. New York, NY:Raven Press; 1996:421-440.
4. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al. ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008; 196:514-522.
5. J.D. Sandy, J. Westling and R.D. Kenagy Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem.2001; 276:13372-13378.
6. Bondeson J, Wainwright S, Hughes C, et al. Clin Exp Rheumatol. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis:a review.2008;26:139-45
7. Jennifer Westling, Amanda J. Fosang, Karena Last,et al. ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain. J. Biol. Chem..2002; 277:6059-16066.
8. Gakuji Hashimoto, Takanori Aoki, Hiroyuki Nakamura, Kazuhiko Tanzawa and Yasunori Okada.Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1,2,3 and 4).FEBS.2007; 494:192-195
9. Differences in the distribution of versican, decorin, and biglycan in atherosclerotic human coronary arteries. Cardiovasc Pathol.1997; 6:271-278.
10. Biglycan, decorin and versican protein expression patterns in coronary arteriopathy of human cardiac allograft:distinctness as compared to native atherosclerosis. JHeart Lung Transplant.1996;15:1233-1247.
11. Kolodgie FD, Burke AP, Farb A, Weber DK, Kutys R, Wight TN, Virmani R. Differential accumulation of proteoglycans and hyaluronan in culprit lesions: insights into plaque erosion. Arterioscler Thromb Vasc Biol.2002; 22: 1642-1648.
12. Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis. Arterioscler Thromb Vase Biol.2002; 22:462-468.
13. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature.2005; 417:750-754.
14. Wight TN, Lara S, Reissen R, LeBaron R, Isner J. Selective deposits of versican in the extracellular matrix of restenotic lesions from human peripheral arteries. Am J Pathol.1997; 151:963-973.
15. R.D. Kenagy, A.H. Plaas and T.N. Wight, Versican degradation and vascular disease, Trends Cardiovasc Med.2006; 16:209-215.
16. Olin KL, Potter-Perigo S, Barrett PHR, Wight TN, Chait A. Lipoprotein lipase enhances the binding of native and oxidized low density lipoproteins to versican and biglycan synthesized by cultured arterial smooth muscle cells. J Biol Chem. 2000; 274:34629-34636.
17. Hamati HF, Britton EL, Carey DJ. Inhibition of proteoglycan synthesis alters extracellular matrix deposition, proliferation, and cytoskeletal organization of rat aortic smooth muscle cells in culture. J Cell Biol.2002; 108:2495-2505.
18. Schonherr E, Jarvelainen HT, Sandell LJ, Wight TN. Effects of platelet-derived growth factor and transforming growth factor-beta 1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells. J Biol Chem..2000;266:17640-17647.
19. Camejo G, Hurt Camejo E, Olsson U, Bondjers G. Proteoglycans and lipoproteins in atherosclerosis. Curr Opin Lipidol..1999;4:385-391.
20. LeBaron RG, Zimmermann DR, Ruoslahti E. Hyaluronate binding properties of versican. J Biol Chem..2002;267:10003-10010
21. Peng-Sheng Zheng, Dana Vais, David LaPierre, Yao-Yun Liang, Vivian Lee, Bing L. Yang and Burton B. Yang. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation. Journal of Cell Science.2004;117:5887-5895
22. PS Zheng, J Wen and LC Ang et al, Versican/PG-M G3 domain promotes tumor growth and angiogenesis, FASEB.J.2004; 18:754-756.
23. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem J.2005; 386:15-27.
24. J.D. Sandy, J. Westling and R.D. Kenagy et al., Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem 2001; 276: 13372-13378.
25. John D. Sandy, Jennifer Westling, Richard D. Kenagy, M. Luisa Iruela-Arispe, Christie Verscharen et al. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem 2001;276:13372-13378.
26. W.H. Yu, S.C. Yu, Q. Meng, K. Brew and J.F. Woessner, Jr...TIMP-3 Binds to Sulfated Glycosaminoglycans of the Extracellular Matrix. J. Biol. Chem.2000; 275:31226-31232
27. M.L. Fitzgerald, Z. Wang, P.W. Park, G. Murphy and M. Bernfield. Shedding of Syndecan-1 and-4 Ectodomains Is Regulated by Multiple Signaling Pathways and Mediated by a Timp-3-Sensitive Metalloproteinase. J. Cell Biol.2005; 148: 811-824
1. Yamagishi M, Terashima M, Awano K, et al.:Morphology of vulnerable coronary plaque:insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. JAm Coll Cardiol 2000, 35:106-111.
2. Loree HM, Kamm RD, Stringfellow RG, Lee RT:Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res 2006,
71:850-858.
3. P. Libby, et al., Inflammation and atherosclerosis, Circulation.2002;105:1135-1143.
4. Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAm Med Assoc 2004;59:2015-2020.
5. James Scott. Pathophysiology and biochemistry of cardiovascular disease. Current Opinion in Genetics & Development 2004,14:271-279
6. Richardson PD, Davies MJ, Born GV. Influence of plaque configura tion and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989;2:1462-1463.
7. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis:characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J.2005;50:127-134.
8. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. JClin Invest.2007;94:2493-2503.
9. Li Z, Li L, Zielke HR, Cheng L, Xiao R, Crow MT, Stetler-Stevenson WG, Froehlich J, Lakatta EG. Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. Am JPathol. 1996;148:121-128.
10. Aimes, R T; Quigley, J P Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4-and 1/4-length fragments. Circ Res 2002;90:251-62.
11.S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem J.2005; 386:15-27.
12. J.D. Sandy, J. Westling and R.D. Kenagy et al, Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinantADAMTS-1 and ADAMTS-4,J Biol Chem.2001; 276: 13372-13378.
13. Jarvelainen H, Wight T. Vascular proteoglycans. Proteoglycans in Lung Disease.. 2002; 15:291-321.
14. Wight TN. Versican:a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol.2002; 14:617-623.
15. R.D. Kenagy, A.H. Plaas and T.N. Wight, Versican degradation and vascular disease, Trends Cardiovasc Med.2006; 16:209-215.
16. B.L. Tang, ADAMTS:a novel family of extracellular matrix proteases, Int J Biochem Cell Biol.2001; 33:33-44.
17. B. Bode-Lesniewska, M.T. Dours-Zimmermann and B.F. Odermatt et al, Distribution of the large aggregating proteoglycan versican in adult human tissues, J Histochem Cytochem.1996; 44:303-312.
18. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, Johan Bjorkegren, Guro Valen, Anders Hamsten and Per Eriksson. ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques Atherosclerosis.2008,196:514-522
19. Jan H. von der Thusen, MD; Theo J.C. van Berkel, PhD; Erik A.L. Biessen, PhD Induction of Rapid Atherogenesis by Peri vascular Carotid Collar Placement in Apolipoprotein E-Deficient and Low-Density Lipoprotein Receptor-Deficient Mice.Circulation.2007; 103:1164-1170
20. Iiyama K, Hajra L, Iiyama M, et al. Patterns of vascular cell adhesion molecule-1 and intercellular molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res.2005;85:199-207.
21. Topper JN, Gimbrone MA Jr. Blood flow and vascular gene expression:fluid shear stress as a modulator of endothelial phenotype. Mol Med Today. 1999;5:40-46.
22. Resnick N, Gimbrone MA Jr. Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J.1995;9:874-882.
23. Korenaga R, Ando J, Kosaki K, et al. Negative transcriptional regulation of the
VCAM-1 gene by fluid shear stress in murine endothelial cells. Am JPhysiol. 1997;273:C1506-1515.
24. Ku DN, Giddens DP, Zarins CK, Glagov S. Pulsatile flow and atherosclerosis in the human carotid bifurcation:positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis.2005;5:293-302.
25. LeBaron RG, Zimmerman DR, Rouslahti E. Hyaluronate binding properties of versican. J Biol Chem.2004;267:10003-10010.
26. Gui Gao, Jennifer Westling, Vivian P. Thompson. Activation of the Proteolytic Activity of ADAMTS4 (Aggrecanase-1) by C-terminal Truncation.J.Biol. Chem.2002; 277:11034-11041
1. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O,Innerarity TL, Boren J:Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 2002,417:750-754.
2. Wentworth P Jr, Nieva J, Takeuchi C, Galve R, Wentworth AD,Dilley RB, DeLaria GA, Saven A, Babior BM, Janda KD et al.:Evidence for ozone formation in human atherosclerotic arteries. Science 2003,302:1053-1056.
3. Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G,Tiret L, Smieja M, Cambien F, Meyer J, Lackner KJ:Glutathione peroxidase 1 activity and cardiovascular events inpatients with coronary artery disease. N Engl J Med 2005,349:1605-1613.
4. Isenberg, J., Calzada, M., Zhou, L., Guo, N., Lawler, J., Wang, X., Frazier, W. and Roberts, D. (2005). Endogenous thrombospondin-1 is not necessary for proliferation but is permissive for vascular smooth muscle cell responses to platelet-derived growth factor. Matrix Biol.2006; 24,110-123
5. Wight, T. N. and Merrilees, M. J. Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ. Res.2004; 94,1158-1167.
6. Merrilees, M. J., Lemire, J. M., Fischer, J. W., Kinsella, M. G, Braun, K. R., Clowes, A. W. and Wight, T. N. Retrovirally mediated overexpression of versican v3 by arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury. Circ. Res.2002; 90, 481-487.
7. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem J.2005; 386:15-27.
8. D.F. Seals and S.A. Courtneidge, The ADAMs family of metalloproteases: multidomain proteins with multiple functions, Genes Dev.2003; 17:7-30
9. B.L. Tang, ADAMTS:a novel family of extracellular matrix proteases, Int J Biochem Cell Biol.2001;33:33-44.
10. Adams, J. C. and Lawler, The thrombospondins. Int. J. Biochem. Cell Biol.2004; 36:961-968. Bornstein, P. Diversity of function is inherent in matricellular proteins:an appraisal of thrombospondin 1. J. Cell Biol1995; 130:503-506.
11. Dixit, V. M., Grant, G. A., Santoro, S. A. and Frazier, W. A. Isolation and characterization of a heparin-binding domain from the amino terminus of platelet thrombospondin. J. Biol. Chem.2000; 259:10100-10105.
12. Hirose, J., Kawashima, H., Yoshie, O., Tashiro, K. and Miyasaka, M. Versican interacts with chemokines and modulates cellular responses. J. Biol. Chem.2001; 276:5228-5234.
13. Kawashima, H., Hirose, M., Hirose, J., Nagakubo, D., Plaas, A. H. and Miyasaka, M. Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin and CD44. J. Biol. Chem.2000; 275:35448-35456.
14. Brooke, B. S., Karnik, S. K. and Li, D. Y. (2003). Extracellular matrix in vascular
morphogenesis and disease:structure versus signal. Trends Cell Biol.2003; 13: 51-56.
15. Fauvel-Lafeve, F. Microfibrils from the arterial subendothelium. Int. Rev. Cytol. 1999; 188:1-40.
16. Fauvel-Lafeve, F., Picard, P., Godeau, G. and Legrand, Y. J.. Characterization of an antibody directed against a 128 kDa glycoprotein involved in the thrombogenicity of the elastin-associated microfibrils. Biochem. J.2009; 255, 251-258.
17. Fauvel-Lafeve, F. and Legrand, Y. J. Immunochemical identification of a thrombospondin-like structure in an arterial microfibrillar extract. Thromb Res. 1998; 50,305-316.
18. Isogai, Z., Aspberg, A., Keene, D. R., Ono, R. N., Reinhardt, D. P. and Sakai, L. Y. Versican interacts with fibrillin-1 and links extracellular microfibrils to other connective tissue networks. J. Biol. Chem.2002; 277:4565-4572.
19. Kelleher, C. M., McLean, S. E. and Mecham, R. P. Vascular extracellular matrix and aortic development. Curr. Top. Dev. Biol.2004; 62:153-188.
20. Lee, T., Nesselroth, S. M., Olson, E. T., Esemuede, N., Lawler, J., Sumpio, B. E. and Gahtan, V. (2003). Thrombospondin-1-induced vascular smooth muscle cell chemotaxis:the role of the type 3 repeat and carboxyl terminal domains. J. Cell Biochem.2003; 89:500-506.
21. Matsumoto, K., Shionyu, M., Go, M., Shimizu, K., Shinomura, T., Kimata, K. and Watanabe, H. (2003). Distinct interaction of versican/PG-M with hyaluronan and link protein. J. Biol. Chem.2004; 278:41205-41212.
22. Wight, T. N. Versican:a versatile extracellular matrix proteoglycan in cell biology. Curr. Opin. Cell Biol.2002; 14:617-623.
23. Yu, H., Tyrrell, D., Cashel, J., Guo, N. H., Vogel, T, Sipes, J. M., Lam, L., Fillit, H. M., Hartman, J., Mendelovitz, S. et al. Specificities of heparin-binding sites from the amino-terminus and type 1 repeats of thrombospondin-1. Arch. Biochem. Biophys.2000; 374:13-23.
24. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, Johan Bjorkegren, Guro Valen, Anders Hamsten,and Per Eriksson ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques.2008; 196:514-522
25. Bjorkerud S, Bjorkerud B.Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages andT-cells), and may contribute to the accumulation of gruel and plaque instability.Am J Pathol 1996; 149:367-380
26. Riessen, R., Kearney, M., Lawler, J. and Isner, J. M.. Immunolocalization of thrombospondin-1 in human atherosclerotic and restenotic arteries. Am. Heart J. 1998; 135,357-364.
1. Bor Luen Tang(2001) ADAMTS:a novel family of extracellular matrix proteases.The International Journal of Biochemistry & Cell Biology.3:33-44.
2. A.C. Newby(2005) Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev.85:1-31.
3.. G.K. Hansson(2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med.352:1685-1695.
4. K. Kuno and K. Matsushima(1998) ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type I motifs and its spacing region. J Biol Chem.273:13912-13917.
5. M. J. Merrilees, B. Beaumont and L. J. Scott (2001) Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency. Coron Artery Dis.12:7-16.
6. L.Y. Yao, C. Moody, E. Schonherr, T.N. Wight, L.J. Sandell(1994) Identification of the proteoglycan versican in aorta and smooth muscle cells by DNA sequence analysis, in situ hybridization and immunohistochemistry. Matrix Biol.14:213-225.
7. A.D. Theocharis, I. Tsolakis, A. Hjerpe and N.K. Karamanos(2001) Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V(0). Atherosclerosis.154:367-376.
8. M. Kashiwagi, M. Tortorella, H. Nagase and K. Brew(2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem.276:12501-12504.
9. G. Gao, J. Westling and V.P. Thompson(2002)Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. J Biol Chem.277:11034-11041.
10. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards(2005)The ADAMTS metalloproteinases. Biochem J.386:15-27.
11. J.D. Sandy, J. Westling and R.D. Kenagy(2002) Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem.276:13372-13378.
12. Apte.SS, Olsen,BR,Murphy.G(1995) The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J. Biol. Chem270:14313-14318.
13. Naito S, Shiomi T, Okada A, Kimura T, Chijiiwa M, Fujita Y, Yatabe T, Komiya K, Enomoto H, Fujikawa K, Okada Y(2007) Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage. Pathol Int.57(11):703-11
14. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, Johan Bjorkegren, Guro Valen, Anders Hamsten(2008)ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.196:514-522.
15..Zorina S. Galis, Jaikirshan J. Khatri (2002).Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly. Circulation Research.90:251.
16. Joanna R. Worley, Mark D. Baugh, David A. Hughes, Dylan R. Edwards, Aileen Hogan, Mike J. Sampson, Jelena Gavrilovic(2003) Metalloproteinase Expression in PMA-stimulated THP-1 Cells effects of peroxisome proliferator-activated receptor-γ(PPARγ) agonists and 9-cis-retinoic acidJ. Biol. Chem.51:51340-51346.
17. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O'Neill WW(2000) Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med.28:915-922.
18. Wysocki L.J., Sato V.L(1978)"Panning" for lymphocytes:a method for cell selection. Proc. Natl. Acad. Sci. U.S.A.75:2844-2848.
19. Hoover M.L., Chapman S.W., Cuchens M.A(1985) A procedure for the isolation of highly purified populations of B cells, T cells and monocytes from human peripheral and umbilical cord blood.J. Immunol. Methods.78:71-85.
20. Kaski JC, Chester MR, Chen L, Katritsis D(1995)Rapid angiographic progression of coronary artery disease in patients with angina pectoris:the role of complex stenosis morphology. Circulation.92:2058-2065.
21. Halpert, I., Sires, U. I., Roby, J. D., Potter-Perigo, S., Wight, T. N., Shapiro, S. D., Welgus, H. G., Wickline, S. A., and Parks, W. C(1996) Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme.Proc. Natl. Acad. Sci. U. S. A.93:9748-9753
22. Evanko, S. P., Raines, E. W., Ross, R., Gold, L. I., and Wight, T. N(1998) Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am. J. Pathol. 152:533-546
23. Joan M. Lemire; Kathleen R. Braun; Patrice Maurel; Elizabeth D. Kaplan; Stephen M. Schwartz; Thomas N. Wight(1999)Versican/PG-M Isoforms in Vascular Smooth Muscle Cells.. Arteriosclerosis, Thrombosis, and Vascular Biology.19:1630-1639.
24. John D. Sandy, Jennifer Westling, Richard D. Kenagy, M. Luisa Iruela-Arispe, Christie (2001)Verscharenl. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem.276:13372-13378.
25. Zorina S. Galis, Jaikirshan J. Khatri(2002) Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly. Circ. Res.90: 251-262
26. P. Libby, P.M. Ridker and A. Maseri (2002) Inflammation and atherosclerosis, Circulation 105:1135-1143.
27. P. R. Brauer(2006) MMPs—role in cardiovascular development and disease, Front Biosci 11:447-478.
28. C. Whatling, H. Bjork, S. Gredmark, A. Hamsten and P. Eriksson(2004) Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes, J Lipid Res.45: 1768-1776.
29. Jude B, Agraou B, McFadden EP(1994) Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina. Circulation.90:1662-8.
30. Divies MJ.(1996) Stability and instability:two faces of coronary atherosclerosis. Circulation.94:2013-20.
31. Schroeder AP, Falk E.(1995)Vulnerable and dangerous coronary plaques. Atherosclerosis.118:S 141-9
32. Wilson RF, Holida MD, White CW(1986) Quantitative angiographic morphology of coronary stenoses leading to myocardial infarction or unstable angina. Circulation.73:286-93.
1. C.P. Blobel, Metalloprotease-disintegrins:links to cell adhesion and cleavage of TNF alpha and Notch, Cell.2003;90:589-592
2. X.P. Zhang, T. Kamata, K. Yokoyama, W. Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3, J. Biol. Chem..2001; 273:7345-7350.
3. F. Loechel, B.J. Gilpin, E. Engvall, R. Albrechtsen and U.M. Wewer, Human ADAM 12 (meltrin alpha) is an active metalloprotease, J. Biol. Chem..1998;273: 16993-16997
4. R.A. Black and J.M. White, ADAMs:focus on the protease domain, Curr. Opin. Cell Biol.1998;10:654-659
5. K. Eto, C. Huet and T. Tarui et al.,Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1:implications for sperm-egg binding and other cell interactions, J. Biol. Chem..2002;277:17804-17810
6. K. Reiss, A. Ludwig and P. Saftig, Breaking up the tie:disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion, Pharmacol. Ther.2006; 111:985-1006
7. S. Takeda, T. Igarashi, H. Mori et al.Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffold, EMBO J 2006;25:2388-2396
8. Nath D,Slocmb PM,Stephens PE et al.Interaction of metargidin(ADAM15)with αvβ3 and α5β1 integrin on different haemopoietic cells. J Cell Sci 2005;112:579-87
9. Kratzschma J,Lum L,Blobel CP. Metargidin-anchored metalloprotease-disintegrin protein with an RGD integrin binding sequence.J Biol Chem 2007;271:4593-6
10. Gawaz MP,Loftus JC,Bajt ML et al.Ligand bridging mediates integrin alpha Ⅱb beta 3 (Platelet GPIIB-IIIA)dependent homotypic and heterotypic cell-cell interactions.J Clin Invest 1991;88:1128-34
11. Lafuste P,Sonnet C,Chazaud B,et al.ADAM12 and alpha9 betal integrin are instrumental in human myogenic cell differentiation. Mol Biol Cell 2005;16:861-70
12. Eto K,Huet C,Tarui T,et al.Functional classification of ADAMs based on a conserved motif for binding to integrin alpha9 beta 1:implications for spermegg binding and other cell interactions. J boil Chem 2002;277:17804-10.
13. A.P. Huovila, E.A. Almeida and J.M. White, ADAMs and cell fusion, Curr. Opin. Cell Biol 1996;8:692-699.
14. A.L. Stone, M. Kroeger and Q.X. Sang, Structure-function analysis of the ADAM family of disintegrin-like and metalloproteinase-containing proteins (review), J. Protein Chem.1999;18::447-465
15. Claudia Andreini, Lucia Banci, Ivano Bertini, Comparative Analysis of the ADAM and ADAMTS Families, J. Proteome Res; 2005;4:881-888,.
16. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem. J.2005;386:15-27.
17. Micky Tortorella, Michael Pratta, Rui-Qin Liu, The Thrombospondin Motif of Aggrecanase-1 (ADAMTS-4) Is Critical for Aggrecan Substrate Recognition and Cleavage, J. Biol. Chem., Vol..2006; 275:25791-25797
18. Guo, N. H., Krutzsch, H. C, Negre, E., Zabrenetzky, V. S., and Roberts, D. D.J. Biol. Chem.1992;267:19349-19355
19. Guo, N. H., Krutzsch, H. C, Negre, E., Vogel, T., Blake, D. A., and Roberts, D. D. Proc. Natl. Acad. Sci. U.SA.2004; 89:3040-3044
20. Kuno, K., Kanada, N., Nakashima, E., Fujiki, F., Ichimura, F., and Matsushima, K. (1997) J. Biol. Chem.2000;272:556-562
21. Kuno, K., and Matsushima, K. J. Biol. Chem.2001.273,13912-13917
22.. L.Y. Yao, C. Moody, E. Schonherr, T.N. Wight.Identification;of the proteoglycan versican in aorta and smooth muscle cells by DNA sequence analysis, in situ hybridization and immunohistochemistry, Matrix Biol.2004; 14:213-225.
23. A.D. Theocharis, I. Tsolakis, A. Hjerpe and N.K. Karamanos, Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V(0), Atherosclerosis.2002;154:367-376.
24. M.J. Merrilees, B. Beaumont and L.J. Scott, Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency, Coron Artery Dis 2007;12:7-16.
25. G.C. Jones and G.P. Riley, ADAMTS proteinases:a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis, Arthritis Res Ther.2005;7:160-169.
26.. Zimmermann DR, Lemire JM, Fischer JW.. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. JBiol Chem.2001; 276: 13372-13378.
27. John D. Sandy, Jennifer Westling, Richard D, Versican V1 Proteolysis in Human Aorta in Vivo Occurs at the Glu441-Ala442 Bond, a Site That Is Cleaved by Recombinant ADAMTS-1 and ADAMTS-4, J. Biol. Chem..2005;276:13372-13378,
28. Tortorella, M. D., Pratta, M., Liu, R. Q., Austin, J., Ross, O. H., Abbaszade, I., Burn, T., and Arner, E. J. Biol. Chem.2000.275,18566-18573
29. Tortorella, M. D., Liu, R.-Q., Burn, T., and Arner, E. Matrix Biol.2002;21: 499-511
30. Patwari, P., Kurz, B., Sandy, J. D., and Grodzinsky, A. J. Arch. Biochem. Biophys. 2000;374:79-85
31. Micky D. Tortorella, Elizabeth C. Arner, Robert Hills, α2-Macroglobulin Is a Novel Substrate for ADAMTS-4 and ADAMTS-5 and Represents an Endogenous Inhibitor of These Enzymes, J. Biol. Chem., Vol.2003;279:17554-17561,
32. Norata GD, Bjork H, Hanmsten A, Catapono AL, Eriksson P. High-density lipoprotein subfraction 3 decreases ADAMTS-1 expression induced by lipopolysaccharide and tumor necrosis factor-alpha in human endothelial cells. Matrix Biol.2004; 22:557-560
33. Z.S. and Khatri, J.J.,2002. Matrix metalloproteinases in vascular remodeling and atherogenesis:the good, the bad, and the ugly. Circ. Res.2002; 90:.251-262.
34. Basile DP, Fredrich K, Chelladurai B, Leonard EC. Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. Am J Physiol Renal Physiol.2008;294:928-36
35..L. Stevens Ph.D, C.A. Wheeler B.S., S.R. Tannenbaum Ph.D. Nitric oxide enhances aggrecan degradation by aggrecanase in response to TNF-but not IL-1β treatment at a post-transcriptional level in bovine cartilage explants.2008,;16: 489-497
36. Dick Wagsaterm, Hanna Bjork, Chaoyong Zhu,ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques,2008; 196:514-522
37. Eli Zamir and Benjamin Geiger, Molecular complexity and dynamics of cell-matrix adhesions, Journal of Cell Science 2001.114:3583-3590
38. Gakuji Hashimoto, Masayuki Shimoda, and Yasunori Okada,ADAMTS4 (Aggrecanase-1) Interaction with the C-terminal Domain of Fibronectin Inhibits Proteolysis of Aggrecan'J. Biol. Chem.,2005;279:32483-32491
39. Masahide Kashiwag, Micky Tortorella, Hideaki Nagase,TIMP-3 Is a Potent Inhibitor of Aggrecanase 1 (ADAM-TS4) and Aggrecanase 2 (ADAM-TS5) J. Biol. Chem..2007; 276:12501-12504.
40. Hashimoto, G., Aoki, T., Nakamura, H., Tanzawa, K., and Okada, Y Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1,2,3 and 4). FEBS Lett.2001;494:192-195
41. Llamazares, M., Cal, S., Quesada, V., and Lopez-Otin, C, ADAMTS4 (Aggrecanase-1) Interaction with the C-terminal Domain of Fibronectin Inhibits Proteolysis of Aggrecan J:Biol. Chem.2003;278:13382-1338.
42. Tontonoz, P., Nagy, L., Alvarez, J. G., Thomazy, V. A., and Evans, R. M. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998;93:241-252
43. Ricote, M., Huang, J., Fajas, L., Li, A., Welch, J., Najib, J., Witztum, J. L. Auwerx, J., Palinski, W., and Glass, C. K. Expression of the peroxisome proliferator-activated receptor γ(PPARγ) in human atherosclerosis and
regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Natl. Acad. Sci. U. S. A 1998;.95:7614-7619
44. Yamanishi, Y., Boyle, D. L., Clark, M., Maki, R. A., Tortorella, M. D., Arner, E. C., and Firestein, G. S. Expression and Regulation of Aggrecanase in Arthritis: The Role of TGF-β() J. Immunol.2002; 168:1405-1412
45. Lam JK, Chion CK, Zanardelli S. Further characterization of AD AMTS-13 inactivation by thrombin.. J Thromb Haemost.2007;5:1010-8.
46. Nadia Al-Fakhri, Jochen Wilhelm, Meinhard Hahn, Increased Expression of Disintegrin-Metalloproteinase ADAM-15 and ADAM-9 Following Upregulation of
47. Integrins a5b1 and avb3 in Atherosclerosis, Journal of Cellular Biochemistry.2003; 89:808-823
48. Vazquez, F., Hastings, G., Ortega, M. A., Lane, T. F. J. Biol. Chem.1999;274: 23349-23357
49. Kuno K, Terashima Y, Matsushima K. AD AMTS-1 is an active metalloprotease associated with the extracellular matrix. JBiol Chem.1999; 274:18821-18826
50. Molloy, S. S., Anderson, E. D., Jean, F., and Thomas, G.. Trends Cell Biol.1999; 9:28-35
51..S. Cal, A.J. Obaya, M. Llamazares, C. Garabaya, V. Quesada and C. Lopez-Otin, Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains, Gene.2002; 283:.49-62.
52. Gui Gao, Jennifer Westling, Vivian P, Activation of the Proteolytic Activity of ADAMTS4 (Aggrecanase-1) by C-terminal Truncation。J. Biol. Chem., 2007;277:11034-11041,
53. Flannery, C. R., Zeng, W., Corcoran, C., Collins-Racie, L. A., Chockalingam, P. S., Hebert, T., Mackie, S. A., McDonagh, T., Crawford, T. K., Tomkinson, K. N., LaVallie, E. R., and Morris, E. A..J. Biol. Chem.2002;277:42775-42780
54. Rodriguez-Manzaneque, J. C, Milchanowski, A. B., Dufour, E. K., Leduc, R., and Iruela-Arispe, M. L. (2000) J. Biol. Chem.275,33471-33479
55. Gao, G., Plaas, A., Thompson, V. P., Jin, S., Zuo, F., and Sandy, J. D. (2004) J. Biol. Chem.279,10042-10051
56. Yamanaka, H., Makino, K., Takizawa, M., Nakamura, H., Fujimoto, N., Moriya, H., Nemori, R., Sato, H., Seiki, M., and Okada, Y. Lab. Investig. 2000;80:677-687
57. Imai, K., Ohta, S., Matsumoto, T., Fujimoto, N., Sato, H., Seiki, M., and Okada, Y. () Am. J. Pathol.2004;151:245-256
58.Kashiwagi, M., Tortorella, M., Nagase, H., and Brew, K. J. Biol. Chem. 2001;276:12501-12504
59. Sandy JD, Westling J, Denegy RD, Iruela-Arispe ML, Verscharen C, Rodriguez-Mazaneque JC, Zimmermann DR, Lemire JM, Fischer JW, Wight TN, Clowes AW. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem.2001; 276:13372-13378
60. Ann-Cathrine Jonsson-Rylander; Tina Nilsson, Role of ADAMTS-1 in Atherosclerosis Remodeling of Carotid Artery, Immunohistochemistry, and Proteolysis of Versican, Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:180
61. S.P. Evanko, J.C. Angello and T.N. Wight, Formation of hyaluronan-and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells, Arterioscler Thromb Vasc Biol.2002;;19:1004-1013.
62. J.M. Lemire, K.R. Braun and P. Maurel et al, Versican/PG-M isoforms in vascular smooth muscle cells, Arterioscler Thromb Vasc Biol 2003;19:1630—1639
63. Izumi, Y., Hirata, M., Hasuwa, H., Iwamoto, R., Umata, T., Miyado, K., Tamai, Y., Kurisaki, T., Sehara-Fujisawa, A., Ohno, S., and Mekada, E. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J.1998 17,7260-7272
64. aab, G., and Klagsbrun, M. Heparin-binding EGF-like growth factor(1997) Biochim. Biophys. Acta 2003;1333:179-199
65. Fukuda, K., Kawata, S., Inui, Y., High Concentration of Glucose Increases Mitogenic Responsiveness to Heparin-Binding Epidermal Growth Factor-like Growth Factor in Rat Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol.2001;17,1962-1968
66. Herren, B., Raines, E. W., and Ross, R. Expression of a disintegrin-like protein in cultured human vascular cells and in vivo.FASEB J.1997;11,173-180
67. Canault M, Peiretti F, Kopp F, Bonardo B, Bonzi MF, Coudeyre JC, Alessi MC, Juhan-Vague I, Nalbone G. The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: possible contribution to elevated plasma levels of soluble TNF alpha receptors. Atherosclerosis.2005.
68. Hidetoshi SATOH, Motoyuki NAKAMURA, Mamoru SATOH,Expression and localization of tumour necrosis factor-and its converting enzyme in human abdominal aortic aneurysm, Clinical Science.2004 106,301-306
69. Matthias Canault, Franck Peiretti, Francis Kopp, The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice:Possible contribution to elevated plasma levels of soluble TNF alpha receptors, Atherosclerosis 2006; 187:82-91
70. P. Libby, P.M. Ridker and A. Maseri, Inflammation and atherosclerosis, Circulation.2002; 105:1135-1143.
71. P.R. Brauer, MMPs—role in cardiovascular development and disease, Front Biosci.2006;11:447-478.
72. C. Whatling, H. Bjork, S. Gredmark, A. Hamsten and P. Eriksson, Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes, J Lipid Res.2004;45:1768-1776.
73. J.D. Sandy, J. Westling and R.D. Kenagy et al., Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, JBiol Chem.2001;276: 13372-13378.
74. R.D. Kenagy, A.H. Plaas and T.N. Wight, Versican degradation and vascular disease, Trends Cardiovasc Med 2006;16:209-215.
75. B. Bode-Lesniewska, M.T. Dours-Zimmermann and B.F. Odermatt et al, Distribution of the large aggregating proteoglycan versican in adult human tissues, J Histochem Cytochem 1996;44:303-312.
76. Perutelli P, Molinari AC, von Willebrand factor, von Willebrand factor-cleaving protease, and shear stress. Cardiovasc Hematol Agents Med Chem. 2007;5:305-10.
77.H. Langer, A.E. May, A. Bultmann and M. Gawaz, AD AM15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation, Thromb Haemost 2005;94:555-561
78. May AE, Kalsch T,Massberg S et al. Engagement of glycoprotein Ⅱb/Ⅲa (αⅡbβ3)on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 2002; 106:2111-7
79. Henn V,Slupsky JR,Grafe M et al.CD40 ligand on activated platelets triggers and inflammatory reaction of endothelial cells.Nature 1998;391:591-51
80. Heeshen C, Dimmeler S, Hamm CW et al. Soluble CD40 ligand in acute coronary syndromes.N Engl J Med 2003;348:1104-11
81. Chion CKNK, Doggen CJM, Crawley JTB,ADAMTS13 and von Willebrand factor and the risk of myocardial infarction in men. BLOOD.2007; 109:1998-2000.
82. Shunichiro Fuchigami, Koichi Kaikita, Kenji Soejima, Changes in plasma Von Willebrand factor-cleaving protease (ADAMTS13) levels in patients with unstable angina Thrombosis Research..2003; 23:432-439.
83. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol.1999; 10: 499-506.
84. Glover C, Ma X, Chen YX. Human in-stent restenosis tissue obtained by means of coronary atherectomy consists of an abundant proteoglycan matrix with a paucity of cell proliferation. Am Heart J.2002; 144:702-709.
85. Euan A. Ashley, MRCP, DPhil; Rossella Ferrara, MD; Network Analysis of Human In-Stent Restenosis. Circulation.2006; 114:2644-2654.
86. Richard D. Kenagy,Anna H. Plaas, and Thomas N. Wight, Versican Degradation and Vascular Disease, Trends in Cardiovascular Medicine.2006;16: 209-215
87. Evanko, S. P., Raines, E. W., Ross, R., Gold, LAm. J. Pathol.1998; 152,533-546
88. Kolodgie, F. D., Burke, A. P., Farb, A., Weber, D. K., Kutys, R.. Arterioscler. Thromb. Vasc. Biol.2002;22:1642-1648.
89._Peng-Sheng Zheng, Dana Vais, David LaPierre, PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation. Journal of Cell Science 2007;117:5887-5895
90. Almeida, E. A., Huovila, A. P., Sutherland, A. E., Stephens, L. E., Calarco, P. G., Shaw, L. M., Mercurio, A. M., Sonnenberg, A., Primakoff, P., Myles, D.G., and White, J. M. Cell.2000; 81:1095-1104
1. PS Zheng, D Vais and D Lapierre et al., PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation, J Cell Sci 2004; 117: 5887-5895
2. Wight,TN Wight and MJ Merrilees, Proteoglycans in atherosclerosis and restenosis:key roles for versican, Circ Res2004; 94:1158-1167.
3. Nikkari.ST Nikkari, HT Jarvelainen and TN Wight et al., Smooth muscle cell expression of extracellular matrix genes after arterial injury,
Am J Pathol.1994; 144:1348-1356
4. Finn, AV Finn, HK Gold and A Tang et al., A novel rat model of carotid artery stenting for the understanding of restenosis in metabolic diseases, J Vasc Res.2002; 39:414-425
5. Kenagy, RD Kenagy, JW Fischer and S Lara et al., Accumulation and loss of extracellular matrix during shear stress-mediated intimal growth and regression in baboon vascular grafts, J Histochem Cytochem.2005; 53:131-140.
6. Chung,IM Chung, HK Gold and SM Schwartz et al., Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment, J Am Coll Cardiol.2002; 40:2072-2081.
7. Farb, A Farb, FD Kolodgie and JY Hwang et al., Extracellular matrix changes in stented human coronary arteries, Circulation.2004; 110: 940-947.
8. Wight, TN Wight, S Lara and R Riessen et al., Selective deposits of versican in the extracellular matrix of restenotic lesions from human peripheral arteries, Am J Pathol1997; 151:963-973.
9. Matsuura,R Matsuura, N Isaka and K Imanaka-Yoshida et al., Deposition of PG-M/versican is a major cause of human coronary restenosis after percutaneous transluminal coronary angioplasty, J Pathol.1996; 180: 311-316.
10. Kolodgie,FD Kolodgie, AP Burke and TN Wight et al., The accumulation of specific types of proteoglycans in eroded plaques:a role in coronary thrombosis in the absence of rupture, Curr Opin Lipidol.2004; 15:575-582.
11. Ujita M, Shinomura T, Ito K, Kitagawa Y, Kimata K. Expression and binding activity of the carboxy-terminal portion of the core protein of PG-M, a large chondroitin sulfate proteoglycan. J Biol Chem. 2000:269:27603-27609.
12. Wight TN. The vascular extracellular matrix. In:Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. New York, NY:Raven Press; 1996:421-440
13. Yamagata M, Saga S, Kato M, Bernfield M, Kimata K. Selective distributions of proteoglycans and their ligands in pericellular matrix of cultured fibroblasts:implications for their roles in cell-substratum adhesion. J Cell Sci.2003;106:55-65.
14. Yamagata M, Suzuki S, Akiyama SK, Yamada KM, Kimata K. Regulation of cell-substrate adhesion by proteoglycans immobilized on extracellular substrates. J Biol Chem.1989:264:8012-8018.
15. Bode-Lesniewska, B., Dours-Zimmermann, M. T., Odermatt, B. F., Briner, J., Heitz, P. U., and Zimmermann, D. R. J. Histochem. Cytochem.2006; 44,303-312
16. Lemire, J. M., Braun, K. R., Maurel, P., Kaplan, E. D., Schwartz, S. M., and Wight, T. N. Arterioscler. Thromb. Vasc. Biol.2001; 19, 1630-1639
17. Yao, L. Y., Moody, C., Schonherr, E., Wight, T. N., and Sandell, L. J. Matrix Biol 1994:14,213-225
18. G Perides, RA Asher and MW Lark et al., Glial hyaluronate-binding protein:a product of metalloproteinase digestion of versican?, Biochem J 1995; 312:377-384.
19. A Passi, D Negrini and R Albertini et al., The sensitivity of versican from rabbit lung to gelatinase A (MMP-2) and B (MMP-9) and its involvement in the development of hydraulic lung edema, FEBS Lett 456 2005; 456:93-96.
20. Halpert et al.1996 I Halpert, UI Sires and JD Roby et al., Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme, Proc Natl Acad
Sci USA 1996:93:9748-9753.
21. Kenagy, RD Kenagy, JW Fischer and MG Davies et al., Increased plasmin and serine proteinase activity during flow-induced intimal atrophy in baboon PTFE grafts, Arterioscler Thromb Vasc Biol 2002; 22: 400-404
22. Sandy, JD Sandy, J Westling and RD Kenagy et al., Versican V1 proteolysis in human aorta in vivo occurs at the Glu445-Ala446 bond a site which is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem 2001; 276:13372-13378
23. Jonsson-Rylander, AC Jonsson-Rylander, T Nilsson and R Fritsche-Danielson et al., Role of ADAMTS-1 in atherosclerosis: remodeling of carotid artery, immunohistochemistry, and proteolysis of versican, Arterioscler Thromb Vasc Biol 2005; 25:180-185.
24. Cross, NA Cross, S Chandrasekharan and N Jokonya et al., The expression and regulation of ADAMTS-1,-4,-5,-9, and-15, and TIMP-3 by TGFbetal in prostate cells:relevance to the accumulation of versican, Prostate.2005; 63:269-275
25. RP Somerville, JM Longpre and KA Jungers et al., Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1, J Biol Chem 2003; 278:9503-9513
26. AC Nicholson, SB Malik and JM Logsdon Jr et al., Functional evolution of ADAMTS genes:evidence from analyses of phylogeny and gene organization, BMC Evol Biol.2005; 5:11
27. MKester, P Waybill and M Kozak, New strategies to prevent restenosis, Am J Cardiovasc Drugs 1 2001; 12:77-83.
28. ST Nikkari, HT Jarvelainen and TN Wight et al., Smooth muscle cell expression of extracellular matrix genes after arterial injury, Am J Pathol 1994; 144:1348-1356
29. VK Nuthakki, PS Fleser and LE Malinzak et al., Lysyl oxidase expression in a rat model of arterial balloon injury, J Vasc Surg.2004; 40:123-129.
30. K Imanaka-Yoshida, R Matsuura and N Isaka et al., Serial extracellular matrix changes in neointimal lesions of human coronary artery after percutaneous transluminal coronary angioplasty:clinical significance of early tenascin-C expression, Virchows Arch Int J Pathol.2001; 439:185-190
31.31. R Matsuura, N Isaka and K Imanaka-Yoshida et al., Deposition of PG-M/versican is a major cause of human coronary restenosis after percutaneous transluminal coronary angioplasty, J Pathol.1996; 180: 311-316
32. RL Geary, ST Nikkari and WD Wagner et al., Wound healing:a paradigm for lumen narrowing after arterial reconstruction, J Vasc Surg.1998; 27:96-106
33. M Asakura, Y Ueda and S Nanto et al., Remodeling of in-stent neointima, which became thinner and transparent over 3 years—serial angiographic and angioscopic follow-up, Circulation.1998; 97: 2003-2006
34. B Langeveld, AJM Roks and RA Tio et al., Rat abdominal aorta stenting: a new and reliable small animal model for in-stent restenosis,J Vasc Res 2004; 41:377-386.
35. Peng-Sheng Zheng, Dana Vais, David LaPierre,et al. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation Journal of Cell Science.2004;117: 5887-5895
36. aneurysmal abdominal aortas, BIOMEDICAL CHROMATOGRAPHY Biomed. Chromatogr.2003; 17:411-416
37. Toole BP, Wight TN, Tammi MI. Hyaluronan-cell interactions in cancer and vascular disease. J Biol Chem.2002; 277:4593-4596.
38. Bourin MC, Lindahl U. Glycosaminoglycans and the regulation of blood coagulation. Biochem J.1993; 289(pt 2):313-330.
39. Camejo G. The interaction of lipids and lipoproteins with the intercellular matrix of arterial tissue:its possible role in atherogenesis. Adv Lipid Res.1982; 19:1-53.
40. Radhakrishnamurthy B, Srinivasan SR, Vijayagopal P, Berenson GS. Arterial wall proteoglycans:biological properties related to pathogenesis of atherosclerosis. Eur Heart J.1990; 11 (suppl E): 148-157.
41. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol.1995; 15:551-561.
42. Kjellen L, Lindahl U. Proteoglycans:structures and interactions. Annu Rev Biochem.1991; 60:443-475
43. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis:the good, the bad, and the ugly. Circ Res.2002; 90:251-262.
44. Gutierrez P,O'Brien KD, Ferguson M, Nikkari ST, Alpers CE, Wight TN. Differences in the distribution of versican, decorin, and biglycan in atherosclerotic human coronary arteries. Cardiovasc Pathol.1997; 6:271-278.
45. Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek J, Virmani R. Coronary plaque erosion without rupture into a lipid core:a frequent cause of coronary thrombosis in sudden coronary death. Circulation. 1996; 93:1354-1363
46. IP Hayward and GR Campbell et al., Relationship of glycosaminoglycan and matrix changes to vascular smooth muscle cell phenotype modulation in rabbit arteries after acute injury,J Vasc Surg 2001; 33:155-164.
47. S Inoue, H Koyama and T Miyata et al., Pathogenetic heterogeneity of in-stent lesion formation in human peripheral arterial disease, J Vasc Surg 2002; 35:672-678.
48. SA Berceli, MG Davies and RD Kenagy et al., Flow-induced neointimal regression in baboon polytetrafluoroethylene grafts is associated with decreased cell proliferation and increased apoptosis,J Vasc Surg 2002; 36:1248-1255
49. EJR Mattsson, TR Kohler and SM Vergel et al., Increased blood flow induces regression of intimal hyperplasia, Arterioscler Thromb Vasc Biol 2007; 17:2245-2249
50. EC Arner, Aggrecanase-mediated cartilage degradation, Curr Opin Pharmacol 2002; 2:322-329
51. W Sheng, GZ Wang and YL Wang et al., The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis, Mol Biol Cell.2005; 16:1330-1340
52. Y Zhang, L Cao and C Kiani et al., Promotion of chondrocyte proliferation by versican mediated by G1 domain and EGF-like motifs, J Cell Biochem.1999; 73:445-457
53. Huang, MJ Merrilees and K Braun et al., Inhibition of versican synthesis by antisense alters smooth muscle cell phenotype and induces elastic fiber formation in vitro and in neointima after vessel injury, Circ Res.2006; 98:370-377
54. SP Evanko, JC Angello and TN Wight, Formation of hyaluronan-and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells, Arterioscler Thromb Vasc Biol.2001;19:1004-1013
55. RT Matthews, SC Gary and C Zerillo et al., Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member, J Biol Chem.2000;275:22695-22703
56. M Formato, M Farina and R Spirito et al., Evidence for a
proinflammatory and proteolytic environment in plaques from endarterectomy segments of human carotid arteries, Arterioscler Thromb Vasc Biol.2003; 24:129-135.
57. Y Zhang, L Cao and BL Yang et al., The G3 domain of versican enhances cell proliferation via epidermal growth factor-like motifs, J Biol Chem 2002; 273:21342-21351
58. PS Zheng, J Wen and LC Ang et al., Versican/PG-M G3 domain promotes tumor growth and angiogenesis, FASEB J. (2004; 18:754-756
59. Y Wu, Y Zhang and L Cao et al., Identification of the motif in versican G3 domain that plays a dominant-negative effect on astrocytoma cell proliferation through inhibiting versican secretion and binding, J Biol Chem.2001; 276:14178-14186.
60. BL Yang, Y Zhang and L Cao et al., Cell adhesion and proliferation mediated through the G1 domain of versican, J Cell Biochem.2003; 72: 210-220
61. Al Olin, M Morgelin and T Sasaki et al., The proteoglycans aggrecan and versican form networks with fibulin-2 through their lectin domain binding, J Biol Chem.2001;276:1253-1261.
62. MJ Merrilees, JM Lemire and JW Fischer et al., Retrovirally mediated overexpression of versican V3 by arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury, Circ Res.2002;90:481-487.
63. JM Lemire, MJ Merrilees and KR Braun et al., Overexpression of the V3 variant of versican alters arterial smooth muscle cell adhesion, migration, and proliferation in vitro, J Cell Physiol.2002;90: 38-45.
64. J Hirose, H Kawashima and 0 Yoshie et al., Versican interacts with chemokines and modulates cellular responses, J Biol Chem.2001;276: 5228-5234
65. H Kawashima, K Atarashi and M Hirose et al., Oversulfated chondroitin/dermatan sulfates containing GlcAbetal/IdoAalphal-3GalNAc (4,6-0-disulfate) interact with L-and P-selectin and chemokines, J Biol Chem.2002;277:12921-12930.
66. M McGee and WD Wagner, Chondroitin sulfate anticoagulant activity is linked to water transfer:relevance to proteoglycan structure in atherosclerosis, Arterioscler Thromb Vasc Biol.2003;23:1921-1927.
67. E Di Cera, Atherosclerosis:testing the water, Arterioscler Thromb Vasc Biol.2003; 23:1713-1714
68.. M Kato, HM Wang and V Kainulainen et al., Physiological degradation converts the soluble syndecan-1 ectodomain from an inhibitor to a potent activator of FGF-2, Nat Med.2004;4:691-697.
69. AB Csoka, GI Frost and R Stern, The six hyaluronidase-like genes in the human and mouse genomes, Matrix Biol 2001:20:499-508.
70. AC Jonsson-Rylander, T Nilsson and R Fritsche-Danielson et al., Role of ADAMTS-1 in atherosclerosis:remodeling of carotid artery, immunohistochemistry, and proteolysis of versican, Arterioscler Thromb Vasc Biol.2005;25:180-185.
2. Raggi P, Achenbach S. Computed tomography for atherosclerosis and coronary artery disease imaging.Discov Med.2010;45:98-104.
3. Ciompi F, Pujol O, Gatta C,et al. Fusing in-vitro and in-vivo intravascular ultrasound data for plaque characterization. Int J Cardiovasc Imaging.2009 Nov 29. [Epub ahead of print]
4. de Korte CL, van der Steen AF, Cepedes El, et al.Characterization of plaque components and vulnerability with intravascular ultrasound elastography. Phys Med Biol.2000 45:1465-75.
5. Takayama T. Can an intravascular imaging modality detect really vulnerable plaque? Circ J. 2010;74(2):252-3.
6. Kubo T, Imanishi T, Kashiwagi M, et al. Multiple coronary lesion instability in patients with acute myocardial infarction as determined by optical coherence tomography. AM J Cardiol. 2010;105:318-22
7. Kilic T, Jneid H, Ural E, Oner G, Sahin T, Kozdag G, Kahraman G, Ural D. Impact of the metabolic syndrome on high-sensitivity C reactive protein levels in patients with acute coronary syndrome. Atherosclerosis.2009;207:591-6.
8. Galan A, Curos A, Valle V.Biomarkers for detection and prediction in acute coronary syndrome. Med Clin (Barc).2009 May 19. [Epub ahead of print].
9. Iversen KK, Dalsgaard M, Teisner AS, Schoos M, Teisner B, Nielsen H, Clemmensen P, Grande P. Usefulness of pregnancy-associated plasma protein A in patients with acute coronary syndrome. Am J Cardiol.2009; 1;104(11):1465-71
10. Shah VK, Shalia KK, Mashru MR, Soneji SL, Abraham A, Kudalkar KV, Vasvani JB, Sanghavi ST. Role of matrix metalloproteinases in coronary artery disease.Indian Heart J. 2009;61(1):44-50.
11..G.C. Jones and G.P. Riley, ADAMTS proteinases:a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis, Arthritis Res Ther 2005; 7: 160-169.
12. B.L. Tang, ADAMTS:a novel family of extracellular matrix proteases, Int J Biochem Cell Biol 2001; 33:33-44.
13. Bor Luen Tang-and Wanjin Hong. ADAMTS:A novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats.FEBS.1999; 445:223-225
14. Claudia Andreini, Lucia Banci, Ivano Bertini, et al. Comparative Analysis of the ADAM and ADAMTS Families J. Proteome Res.2005;4:881-888..
15. M. Kashiwagi, M. Tortorella, H. Nagase and K. et al.TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5), JBiol Chem 2001; 276: 12501-12504.
16. Nadia Al-Fakhri, Jochen Wilhelm, Meinhard Hahn. Increased Expression of Disintegrin-Metalloproteinases ADAM-15 and ADAM-9 Following Upregulation of Integrins a5b1 and avb3 in Atherosclerosis.Journal of Cellular Biochemistry.2003;89:808-823
17. Ok-Hee Jeon 1, Dongbum Kim 1, Yong-Jun Choi,et al. Novel function of human ADAM 15 disintegrin-like domain and its derivatives in platelet aggregation. Thrombosis Research.2007; 119:609—619
18. Micky Tortorella, Michael Pratta, Rui-Qin Liu et al. The Thrombospondin Motif of Aggrecanase-1 (ADAMTS-4) Is Critical for Aggrecan Substrate Recognition and Cleavage J. Biol. Chem..2000; 275:25791-25797.
19. Svetlana A. Kuznetsova, Philip Issa. Versican-thrombospondin-1 binding in vitro and colocalization in microfibrils induced by inflammation on vascular smooth muscle cells Journal of Cell Science.2006; 119:4499-4509
20. Bondeson J, Wainwright S, Hughes C, et al. Clin Exp Rheumatol. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis:a review.2008;26:139-45
21. Jennifer Westling, Amanda J. Fosang, Karena Last,et al. ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain. J. Biol. Chem..2002; 277: 6059-16066.
22. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al. ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008; 196:514-522.
23. Celik T, Iyisoy A, Kardesoglu E, Bugan B, Isik E. Matrix metalloproteinases in acute coronary syndromes:a new therapeutic target. Int J Cardiol.2009 May 29;134(3):402-4
24. Merrilees MJ, Beaumont B, Scott LJ. Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency. Coron Artery Dis.2001; 12:7-16.
25. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2001; 21:1053-1058
26. Olin AI, Morgelin M, Sasaki T, Timpl R, Heinegard D, Asperg A. The proteoglycan aggrecan and versican form networks with fibulin-2 through their lectin domain binding. JBiol Chem. 2001; 276:1253-1261
27. Theocharis AD, Tsolakis I, Hjerpe A, Karamanos NK. Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V0. Atherosclerosis.2001; 154:367-376.
28. J.D. Sandy, J. Westling and R.D. Kenagy Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, JBiol Chem.2001; 276:13372-13378.
29. Yaou Zhang, Liu Cao, Bing L. Yang, and Burton B. Yang.The G3 Domain of Versican Enhances Cell Proliferation via Epidermial Growth Factor-like Motifs. J Biol Chem. 1998;273:21342-21351.
30. Peng-Sheng Zheng, Dana Vais, David LaPierre,et al. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation.Journal/of Cell Science.2004;117: 5887-5895
31. Gakuji Hashimoto, Takanori Aoki, Hiroyuki Nakamura,et al. Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1,2,3 and 4) FEBS.2001;494:192-195
32. Ann-Cathrine Jonsson-Rylander; Tina Nilsson; Regina Fritsche-Danielson, et al. Role of ADAMTS-1 in Atherosclerosis Remodeling of Carotid Artery, Immunohistochemistry, and Proteolysis of Versican Arteriosclerosis, Thrombosis, and Vascular Biology.2005;25:180.-185
1. Bor Luen Tang.ADAMTS:a novel family of extracellular matrix proteases.The International Journal of Biochemistry & Cell Biology.2001;3:33-44.
2. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards.The ADAMTS metalloproteinases, Biochem J 2005;386:15-27.
3. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al.ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008;196:514-522.
4. Richard D. Kenagy, Anna H. Plaas and Thomas N. Wight.Versican Degradation and Vascular Disease.Trends in Cardiovascular Medicine.2006; 16:209-215
5. J.D. Sandy, J. Westling and R.D. Kenagy Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem.2001; 276:13372-13378.
6. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2005; 21:1053-1058
7. Joanna R. Worley, Mark D. Baugh, David A. Hughes, Dylan R. Edwards, Aileen Hogan, Mike J. Sampson, Jelena GavrilovicMetalloproteinase Expression in PMA-stimulatedTHP-1 cells effects of peroxisome proliferator-activated receptor-THP-1-γ (PPARγ) agonists and 9-cis-retinoic acid J. Biol. Chem. 2003;51:51340-51346
8. Yaou Zhang, Liu Cao, Bing L. Yang, and Burton B. Yang.The G3 Domain of Versican Enhances Cell Proliferation via Epidermial Growth Factor-like Motifs. J Biol Chem.1998;273:21342-21351.
9. Peng-Sheng Zheng, Dana Vais, David LaPierre,et al. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation.Journal of Cell Science.2004;117:5887-5895
10. eLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves:a nonparametric approach. Biometrics.2006;.44:837-45.
11. hah VK, Shalia KK, Mashru MR, Soneji SL, Abraham A, Kudalkar KV, Vasvani JB, Sanghavi ST. Role of matrix metalloproteinases in coronary artery disease.Indian Heart J.2009;61(1):44-50.
12. lin AI, Morgelin M, Sasaki T, Timpl R, Heinegard D, Asperg A. The proteoglycan aggrecan and versican form networks with fibulin-2 through their lectin domain binding. J Biol Chem.2001; 276:1253-1261
13. heocharis AD, Tsolakis I, Hjerpe A, Karamanos NK. Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V0. Atherosclerosis.2001; 154:367-376.
14. errilees MJ, Beaumont B, Scott LJ. Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries: correlation to patency. Cor on Artery Dis.2001; 12:7-16.
15. akala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2001; 21:1053-1058
16. ennifer Westling, Amanda J. Fosang, Karena Last,et al. ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain. J. Biol. Chem..2002; 277:6059-16066.
17. Zorina S. Galis, Jaikirshan J. Khatri.Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly Circulation Research.2004; 90:251.
18..K. Reiss, A. Ludwig, P. Saftig.Breaking up the tie:disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacol. Ther.2006; 111:985-1006
19. vanko, S. P., Raines, E. W., Ross, R., Gold, L. I., and Wight, T. N. Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am. J. Pathol.1998; 152:533-546.
20. irmani R, Burke AP, Farb A.(1999) Plaque rupture and plaque erosion. Thromb Haemost.1999; 82:1-3.
21. Zorina S. Galis, Jaikirshan J. Khatri. Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly.. Circ. Res. 2002; 90:251-262
1. Lijnen, H. R., J. Silence, G. Lemmens, L. Frederix, and D. Collen. Regulation of gelatinase activity in mice with targeted inactivation of components of the plasminogen/plasmin system. Thromb. Haemost.1998;79:1171-1176.
2. Galis, Z. S., G. K. Sukhova, R. Kranzhofer, S. Clark, and P. Libby. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc. Natl. Acad. Sci. USA.1995;92:402—406.
3..Zorina S. Galis, Jaikirshan J. Khatri.Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly. Circulation Research.2002;90:251.
4. Joanna R. Worley, Mark D. Baugh, David A. Hughes, Dylan R. Edwards, Aileen Hogan, Mike J. Sampson, Jelena Gavrilovic. Metalloproteinase Expression in PMA-stimulated THP-1 Cells effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonists and 9-cis-retinoic acid. J. Biol. Chem.2003;51: 51340-51346.
5. Goldstein JA, Demetriou D, Grines CL, et al.Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med.2000;28:915-922.
6. Kaski JC, Chester MR, Chen L, Katritsis D.Rapid angiographic progression of coronary artery disease in patients with angina pectoris:the role of complex stenosis morphology. Circulation.2005;92:2058-2065.
7. Sullivan DR, Marwick TH, Freedman SB. A new method of scoring coronary angiograms to reflect extent of coronary atherosclerosis and improve correlation with major risk factors. Am Heart J 1990;119:1262-7.
8. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al.ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008;196:514-522.
9. Richard D. Kenagy, Anna H. Plaas and Thomas N. Wight. Versican Degradation and Vascular Disease.Trends in Cardiovascular Medicine.2006; 16:209-215
10. R. Worley, M.D. Baugh and D.A. Hughes et al., Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid, JBiol Chem. 2003;278:51340-51346.
11. Uma Singh, Sridevi Devaraj and Ishwarlal Jialal C-Reactive Protein Stimulates Myeloperoxidase Release from Polymorphonuclear Cells and Monocytes: Implications for Acute Coronary Syndromes.. Clinical Chemistry 2009;55: 361-364.
12. Divies MJ. Stability and instability:two faces of coronaryatherosclerosis.Circulation.2002;94:2013-20.
13. Schroeder AP, Falk E.Vulnerable and dangerous coronary plaques. Atherosclerosis.2006; 118:S 141-9
14. Wilson RF, Holida MD, White CW. Quantitative angiographic morphology of coronary stenoses leading to myocardial infarction or unstable angina. Circulation.1999; 73:286-93.
15. Katritsis D, Korovesis S, Giazitzoglou E, et al. C-Reactive protein concentrations and angiographic characteristics of coronary lesions.Clin Chem 2005;47(5):882-
1. Merrilees MJ, Beaumont B, Scott LJ. Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency. Coron Artery Dis.2001; 12:7-16.
2. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb VascBiol.2003; 21:1053-1058
3. Wight TN. The vascular extracellular matrix. In:Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. New York, NY:Raven Press; 1996:421-440.
4. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, et al. ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.2008; 196:514-522.
5. J.D. Sandy, J. Westling and R.D. Kenagy Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem.2001; 276:13372-13378.
6. Bondeson J, Wainwright S, Hughes C, et al. Clin Exp Rheumatol. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis:a review.2008;26:139-45
7. Jennifer Westling, Amanda J. Fosang, Karena Last,et al. ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain. J. Biol. Chem..2002; 277:6059-16066.
8. Gakuji Hashimoto, Takanori Aoki, Hiroyuki Nakamura, Kazuhiko Tanzawa and Yasunori Okada.Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1,2,3 and 4).FEBS.2007; 494:192-195
9. Differences in the distribution of versican, decorin, and biglycan in atherosclerotic human coronary arteries. Cardiovasc Pathol.1997; 6:271-278.
10. Biglycan, decorin and versican protein expression patterns in coronary arteriopathy of human cardiac allograft:distinctness as compared to native atherosclerosis. JHeart Lung Transplant.1996;15:1233-1247.
11. Kolodgie FD, Burke AP, Farb A, Weber DK, Kutys R, Wight TN, Virmani R. Differential accumulation of proteoglycans and hyaluronan in culprit lesions: insights into plaque erosion. Arterioscler Thromb Vasc Biol.2002; 22: 1642-1648.
12. Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis. Arterioscler Thromb Vase Biol.2002; 22:462-468.
13. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature.2005; 417:750-754.
14. Wight TN, Lara S, Reissen R, LeBaron R, Isner J. Selective deposits of versican in the extracellular matrix of restenotic lesions from human peripheral arteries. Am J Pathol.1997; 151:963-973.
15. R.D. Kenagy, A.H. Plaas and T.N. Wight, Versican degradation and vascular disease, Trends Cardiovasc Med.2006; 16:209-215.
16. Olin KL, Potter-Perigo S, Barrett PHR, Wight TN, Chait A. Lipoprotein lipase enhances the binding of native and oxidized low density lipoproteins to versican and biglycan synthesized by cultured arterial smooth muscle cells. J Biol Chem. 2000; 274:34629-34636.
17. Hamati HF, Britton EL, Carey DJ. Inhibition of proteoglycan synthesis alters extracellular matrix deposition, proliferation, and cytoskeletal organization of rat aortic smooth muscle cells in culture. J Cell Biol.2002; 108:2495-2505.
18. Schonherr E, Jarvelainen HT, Sandell LJ, Wight TN. Effects of platelet-derived growth factor and transforming growth factor-beta 1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells. J Biol Chem..2000;266:17640-17647.
19. Camejo G, Hurt Camejo E, Olsson U, Bondjers G. Proteoglycans and lipoproteins in atherosclerosis. Curr Opin Lipidol..1999;4:385-391.
20. LeBaron RG, Zimmermann DR, Ruoslahti E. Hyaluronate binding properties of versican. J Biol Chem..2002;267:10003-10010
21. Peng-Sheng Zheng, Dana Vais, David LaPierre, Yao-Yun Liang, Vivian Lee, Bing L. Yang and Burton B. Yang. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation. Journal of Cell Science.2004;117:5887-5895
22. PS Zheng, J Wen and LC Ang et al, Versican/PG-M G3 domain promotes tumor growth and angiogenesis, FASEB.J.2004; 18:754-756.
23. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem J.2005; 386:15-27.
24. J.D. Sandy, J. Westling and R.D. Kenagy et al., Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem 2001; 276: 13372-13378.
25. John D. Sandy, Jennifer Westling, Richard D. Kenagy, M. Luisa Iruela-Arispe, Christie Verscharen et al. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem 2001;276:13372-13378.
26. W.H. Yu, S.C. Yu, Q. Meng, K. Brew and J.F. Woessner, Jr...TIMP-3 Binds to Sulfated Glycosaminoglycans of the Extracellular Matrix. J. Biol. Chem.2000; 275:31226-31232
27. M.L. Fitzgerald, Z. Wang, P.W. Park, G. Murphy and M. Bernfield. Shedding of Syndecan-1 and-4 Ectodomains Is Regulated by Multiple Signaling Pathways and Mediated by a Timp-3-Sensitive Metalloproteinase. J. Cell Biol.2005; 148: 811-824
1. Yamagishi M, Terashima M, Awano K, et al.:Morphology of vulnerable coronary plaque:insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. JAm Coll Cardiol 2000, 35:106-111.
2. Loree HM, Kamm RD, Stringfellow RG, Lee RT:Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res 2006,
71:850-858.
3. P. Libby, et al., Inflammation and atherosclerosis, Circulation.2002;105:1135-1143.
4. Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAm Med Assoc 2004;59:2015-2020.
5. James Scott. Pathophysiology and biochemistry of cardiovascular disease. Current Opinion in Genetics & Development 2004,14:271-279
6. Richardson PD, Davies MJ, Born GV. Influence of plaque configura tion and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989;2:1462-1463.
7. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis:characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J.2005;50:127-134.
8. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. JClin Invest.2007;94:2493-2503.
9. Li Z, Li L, Zielke HR, Cheng L, Xiao R, Crow MT, Stetler-Stevenson WG, Froehlich J, Lakatta EG. Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. Am JPathol. 1996;148:121-128.
10. Aimes, R T; Quigley, J P Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4-and 1/4-length fragments. Circ Res 2002;90:251-62.
11.S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem J.2005; 386:15-27.
12. J.D. Sandy, J. Westling and R.D. Kenagy et al, Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinantADAMTS-1 and ADAMTS-4,J Biol Chem.2001; 276: 13372-13378.
13. Jarvelainen H, Wight T. Vascular proteoglycans. Proteoglycans in Lung Disease.. 2002; 15:291-321.
14. Wight TN. Versican:a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol.2002; 14:617-623.
15. R.D. Kenagy, A.H. Plaas and T.N. Wight, Versican degradation and vascular disease, Trends Cardiovasc Med.2006; 16:209-215.
16. B.L. Tang, ADAMTS:a novel family of extracellular matrix proteases, Int J Biochem Cell Biol.2001; 33:33-44.
17. B. Bode-Lesniewska, M.T. Dours-Zimmermann and B.F. Odermatt et al, Distribution of the large aggregating proteoglycan versican in adult human tissues, J Histochem Cytochem.1996; 44:303-312.
18. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, Johan Bjorkegren, Guro Valen, Anders Hamsten and Per Eriksson. ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques Atherosclerosis.2008,196:514-522
19. Jan H. von der Thusen, MD; Theo J.C. van Berkel, PhD; Erik A.L. Biessen, PhD Induction of Rapid Atherogenesis by Peri vascular Carotid Collar Placement in Apolipoprotein E-Deficient and Low-Density Lipoprotein Receptor-Deficient Mice.Circulation.2007; 103:1164-1170
20. Iiyama K, Hajra L, Iiyama M, et al. Patterns of vascular cell adhesion molecule-1 and intercellular molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res.2005;85:199-207.
21. Topper JN, Gimbrone MA Jr. Blood flow and vascular gene expression:fluid shear stress as a modulator of endothelial phenotype. Mol Med Today. 1999;5:40-46.
22. Resnick N, Gimbrone MA Jr. Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J.1995;9:874-882.
23. Korenaga R, Ando J, Kosaki K, et al. Negative transcriptional regulation of the
VCAM-1 gene by fluid shear stress in murine endothelial cells. Am JPhysiol. 1997;273:C1506-1515.
24. Ku DN, Giddens DP, Zarins CK, Glagov S. Pulsatile flow and atherosclerosis in the human carotid bifurcation:positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis.2005;5:293-302.
25. LeBaron RG, Zimmerman DR, Rouslahti E. Hyaluronate binding properties of versican. J Biol Chem.2004;267:10003-10010.
26. Gui Gao, Jennifer Westling, Vivian P. Thompson. Activation of the Proteolytic Activity of ADAMTS4 (Aggrecanase-1) by C-terminal Truncation.J.Biol. Chem.2002; 277:11034-11041
1. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O,Innerarity TL, Boren J:Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 2002,417:750-754.
2. Wentworth P Jr, Nieva J, Takeuchi C, Galve R, Wentworth AD,Dilley RB, DeLaria GA, Saven A, Babior BM, Janda KD et al.:Evidence for ozone formation in human atherosclerotic arteries. Science 2003,302:1053-1056.
3. Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G,Tiret L, Smieja M, Cambien F, Meyer J, Lackner KJ:Glutathione peroxidase 1 activity and cardiovascular events inpatients with coronary artery disease. N Engl J Med 2005,349:1605-1613.
4. Isenberg, J., Calzada, M., Zhou, L., Guo, N., Lawler, J., Wang, X., Frazier, W. and Roberts, D. (2005). Endogenous thrombospondin-1 is not necessary for proliferation but is permissive for vascular smooth muscle cell responses to platelet-derived growth factor. Matrix Biol.2006; 24,110-123
5. Wight, T. N. and Merrilees, M. J. Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ. Res.2004; 94,1158-1167.
6. Merrilees, M. J., Lemire, J. M., Fischer, J. W., Kinsella, M. G, Braun, K. R., Clowes, A. W. and Wight, T. N. Retrovirally mediated overexpression of versican v3 by arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury. Circ. Res.2002; 90, 481-487.
7. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem J.2005; 386:15-27.
8. D.F. Seals and S.A. Courtneidge, The ADAMs family of metalloproteases: multidomain proteins with multiple functions, Genes Dev.2003; 17:7-30
9. B.L. Tang, ADAMTS:a novel family of extracellular matrix proteases, Int J Biochem Cell Biol.2001;33:33-44.
10. Adams, J. C. and Lawler, The thrombospondins. Int. J. Biochem. Cell Biol.2004; 36:961-968. Bornstein, P. Diversity of function is inherent in matricellular proteins:an appraisal of thrombospondin 1. J. Cell Biol1995; 130:503-506.
11. Dixit, V. M., Grant, G. A., Santoro, S. A. and Frazier, W. A. Isolation and characterization of a heparin-binding domain from the amino terminus of platelet thrombospondin. J. Biol. Chem.2000; 259:10100-10105.
12. Hirose, J., Kawashima, H., Yoshie, O., Tashiro, K. and Miyasaka, M. Versican interacts with chemokines and modulates cellular responses. J. Biol. Chem.2001; 276:5228-5234.
13. Kawashima, H., Hirose, M., Hirose, J., Nagakubo, D., Plaas, A. H. and Miyasaka, M. Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin and CD44. J. Biol. Chem.2000; 275:35448-35456.
14. Brooke, B. S., Karnik, S. K. and Li, D. Y. (2003). Extracellular matrix in vascular
morphogenesis and disease:structure versus signal. Trends Cell Biol.2003; 13: 51-56.
15. Fauvel-Lafeve, F. Microfibrils from the arterial subendothelium. Int. Rev. Cytol. 1999; 188:1-40.
16. Fauvel-Lafeve, F., Picard, P., Godeau, G. and Legrand, Y. J.. Characterization of an antibody directed against a 128 kDa glycoprotein involved in the thrombogenicity of the elastin-associated microfibrils. Biochem. J.2009; 255, 251-258.
17. Fauvel-Lafeve, F. and Legrand, Y. J. Immunochemical identification of a thrombospondin-like structure in an arterial microfibrillar extract. Thromb Res. 1998; 50,305-316.
18. Isogai, Z., Aspberg, A., Keene, D. R., Ono, R. N., Reinhardt, D. P. and Sakai, L. Y. Versican interacts with fibrillin-1 and links extracellular microfibrils to other connective tissue networks. J. Biol. Chem.2002; 277:4565-4572.
19. Kelleher, C. M., McLean, S. E. and Mecham, R. P. Vascular extracellular matrix and aortic development. Curr. Top. Dev. Biol.2004; 62:153-188.
20. Lee, T., Nesselroth, S. M., Olson, E. T., Esemuede, N., Lawler, J., Sumpio, B. E. and Gahtan, V. (2003). Thrombospondin-1-induced vascular smooth muscle cell chemotaxis:the role of the type 3 repeat and carboxyl terminal domains. J. Cell Biochem.2003; 89:500-506.
21. Matsumoto, K., Shionyu, M., Go, M., Shimizu, K., Shinomura, T., Kimata, K. and Watanabe, H. (2003). Distinct interaction of versican/PG-M with hyaluronan and link protein. J. Biol. Chem.2004; 278:41205-41212.
22. Wight, T. N. Versican:a versatile extracellular matrix proteoglycan in cell biology. Curr. Opin. Cell Biol.2002; 14:617-623.
23. Yu, H., Tyrrell, D., Cashel, J., Guo, N. H., Vogel, T, Sipes, J. M., Lam, L., Fillit, H. M., Hartman, J., Mendelovitz, S. et al. Specificities of heparin-binding sites from the amino-terminus and type 1 repeats of thrombospondin-1. Arch. Biochem. Biophys.2000; 374:13-23.
24. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, Johan Bjorkegren, Guro Valen, Anders Hamsten,and Per Eriksson ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques.2008; 196:514-522
25. Bjorkerud S, Bjorkerud B.Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages andT-cells), and may contribute to the accumulation of gruel and plaque instability.Am J Pathol 1996; 149:367-380
26. Riessen, R., Kearney, M., Lawler, J. and Isner, J. M.. Immunolocalization of thrombospondin-1 in human atherosclerotic and restenotic arteries. Am. Heart J. 1998; 135,357-364.
1. Bor Luen Tang(2001) ADAMTS:a novel family of extracellular matrix proteases.The International Journal of Biochemistry & Cell Biology.3:33-44.
2. A.C. Newby(2005) Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev.85:1-31.
3.. G.K. Hansson(2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med.352:1685-1695.
4. K. Kuno and K. Matsushima(1998) ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type I motifs and its spacing region. J Biol Chem.273:13912-13917.
5. M. J. Merrilees, B. Beaumont and L. J. Scott (2001) Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency. Coron Artery Dis.12:7-16.
6. L.Y. Yao, C. Moody, E. Schonherr, T.N. Wight, L.J. Sandell(1994) Identification of the proteoglycan versican in aorta and smooth muscle cells by DNA sequence analysis, in situ hybridization and immunohistochemistry. Matrix Biol.14:213-225.
7. A.D. Theocharis, I. Tsolakis, A. Hjerpe and N.K. Karamanos(2001) Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V(0). Atherosclerosis.154:367-376.
8. M. Kashiwagi, M. Tortorella, H. Nagase and K. Brew(2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem.276:12501-12504.
9. G. Gao, J. Westling and V.P. Thompson(2002)Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. J Biol Chem.277:11034-11041.
10. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards(2005)The ADAMTS metalloproteinases. Biochem J.386:15-27.
11. J.D. Sandy, J. Westling and R.D. Kenagy(2002) Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem.276:13372-13378.
12. Apte.SS, Olsen,BR,Murphy.G(1995) The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J. Biol. Chem270:14313-14318.
13. Naito S, Shiomi T, Okada A, Kimura T, Chijiiwa M, Fujita Y, Yatabe T, Komiya K, Enomoto H, Fujikawa K, Okada Y(2007) Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage. Pathol Int.57(11):703-11
14. Dick Wagsater, Hanna Bjork, Chaoyong Zhu, Johan Bjorkegren, Guro Valen, Anders Hamsten(2008)ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis.196:514-522.
15..Zorina S. Galis, Jaikirshan J. Khatri (2002).Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly. Circulation Research.90:251.
16. Joanna R. Worley, Mark D. Baugh, David A. Hughes, Dylan R. Edwards, Aileen Hogan, Mike J. Sampson, Jelena Gavrilovic(2003) Metalloproteinase Expression in PMA-stimulated THP-1 Cells effects of peroxisome proliferator-activated receptor-γ(PPARγ) agonists and 9-cis-retinoic acidJ. Biol. Chem.51:51340-51346.
17. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O'Neill WW(2000) Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med.28:915-922.
18. Wysocki L.J., Sato V.L(1978)"Panning" for lymphocytes:a method for cell selection. Proc. Natl. Acad. Sci. U.S.A.75:2844-2848.
19. Hoover M.L., Chapman S.W., Cuchens M.A(1985) A procedure for the isolation of highly purified populations of B cells, T cells and monocytes from human peripheral and umbilical cord blood.J. Immunol. Methods.78:71-85.
20. Kaski JC, Chester MR, Chen L, Katritsis D(1995)Rapid angiographic progression of coronary artery disease in patients with angina pectoris:the role of complex stenosis morphology. Circulation.92:2058-2065.
21. Halpert, I., Sires, U. I., Roby, J. D., Potter-Perigo, S., Wight, T. N., Shapiro, S. D., Welgus, H. G., Wickline, S. A., and Parks, W. C(1996) Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme.Proc. Natl. Acad. Sci. U. S. A.93:9748-9753
22. Evanko, S. P., Raines, E. W., Ross, R., Gold, L. I., and Wight, T. N(1998) Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am. J. Pathol. 152:533-546
23. Joan M. Lemire; Kathleen R. Braun; Patrice Maurel; Elizabeth D. Kaplan; Stephen M. Schwartz; Thomas N. Wight(1999)Versican/PG-M Isoforms in Vascular Smooth Muscle Cells.. Arteriosclerosis, Thrombosis, and Vascular Biology.19:1630-1639.
24. John D. Sandy, Jennifer Westling, Richard D. Kenagy, M. Luisa Iruela-Arispe, Christie (2001)Verscharenl. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem.276:13372-13378.
25. Zorina S. Galis, Jaikirshan J. Khatri(2002) Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis The Good, the Bad, and the Ugly. Circ. Res.90: 251-262
26. P. Libby, P.M. Ridker and A. Maseri (2002) Inflammation and atherosclerosis, Circulation 105:1135-1143.
27. P. R. Brauer(2006) MMPs—role in cardiovascular development and disease, Front Biosci 11:447-478.
28. C. Whatling, H. Bjork, S. Gredmark, A. Hamsten and P. Eriksson(2004) Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes, J Lipid Res.45: 1768-1776.
29. Jude B, Agraou B, McFadden EP(1994) Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina. Circulation.90:1662-8.
30. Divies MJ.(1996) Stability and instability:two faces of coronary atherosclerosis. Circulation.94:2013-20.
31. Schroeder AP, Falk E.(1995)Vulnerable and dangerous coronary plaques. Atherosclerosis.118:S 141-9
32. Wilson RF, Holida MD, White CW(1986) Quantitative angiographic morphology of coronary stenoses leading to myocardial infarction or unstable angina. Circulation.73:286-93.
1. C.P. Blobel, Metalloprotease-disintegrins:links to cell adhesion and cleavage of TNF alpha and Notch, Cell.2003;90:589-592
2. X.P. Zhang, T. Kamata, K. Yokoyama, W. Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3, J. Biol. Chem..2001; 273:7345-7350.
3. F. Loechel, B.J. Gilpin, E. Engvall, R. Albrechtsen and U.M. Wewer, Human ADAM 12 (meltrin alpha) is an active metalloprotease, J. Biol. Chem..1998;273: 16993-16997
4. R.A. Black and J.M. White, ADAMs:focus on the protease domain, Curr. Opin. Cell Biol.1998;10:654-659
5. K. Eto, C. Huet and T. Tarui et al.,Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1:implications for sperm-egg binding and other cell interactions, J. Biol. Chem..2002;277:17804-17810
6. K. Reiss, A. Ludwig and P. Saftig, Breaking up the tie:disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion, Pharmacol. Ther.2006; 111:985-1006
7. S. Takeda, T. Igarashi, H. Mori et al.Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffold, EMBO J 2006;25:2388-2396
8. Nath D,Slocmb PM,Stephens PE et al.Interaction of metargidin(ADAM15)with αvβ3 and α5β1 integrin on different haemopoietic cells. J Cell Sci 2005;112:579-87
9. Kratzschma J,Lum L,Blobel CP. Metargidin-anchored metalloprotease-disintegrin protein with an RGD integrin binding sequence.J Biol Chem 2007;271:4593-6
10. Gawaz MP,Loftus JC,Bajt ML et al.Ligand bridging mediates integrin alpha Ⅱb beta 3 (Platelet GPIIB-IIIA)dependent homotypic and heterotypic cell-cell interactions.J Clin Invest 1991;88:1128-34
11. Lafuste P,Sonnet C,Chazaud B,et al.ADAM12 and alpha9 betal integrin are instrumental in human myogenic cell differentiation. Mol Biol Cell 2005;16:861-70
12. Eto K,Huet C,Tarui T,et al.Functional classification of ADAMs based on a conserved motif for binding to integrin alpha9 beta 1:implications for spermegg binding and other cell interactions. J boil Chem 2002;277:17804-10.
13. A.P. Huovila, E.A. Almeida and J.M. White, ADAMs and cell fusion, Curr. Opin. Cell Biol 1996;8:692-699.
14. A.L. Stone, M. Kroeger and Q.X. Sang, Structure-function analysis of the ADAM family of disintegrin-like and metalloproteinase-containing proteins (review), J. Protein Chem.1999;18::447-465
15. Claudia Andreini, Lucia Banci, Ivano Bertini, Comparative Analysis of the ADAM and ADAMTS Families, J. Proteome Res; 2005;4:881-888,.
16. S. Porter, I.M. Clark, L. Kevorkian and D.R. Edwards, The ADAMTS metalloproteinases, Biochem. J.2005;386:15-27.
17. Micky Tortorella, Michael Pratta, Rui-Qin Liu, The Thrombospondin Motif of Aggrecanase-1 (ADAMTS-4) Is Critical for Aggrecan Substrate Recognition and Cleavage, J. Biol. Chem., Vol..2006; 275:25791-25797
18. Guo, N. H., Krutzsch, H. C, Negre, E., Zabrenetzky, V. S., and Roberts, D. D.J. Biol. Chem.1992;267:19349-19355
19. Guo, N. H., Krutzsch, H. C, Negre, E., Vogel, T., Blake, D. A., and Roberts, D. D. Proc. Natl. Acad. Sci. U.SA.2004; 89:3040-3044
20. Kuno, K., Kanada, N., Nakashima, E., Fujiki, F., Ichimura, F., and Matsushima, K. (1997) J. Biol. Chem.2000;272:556-562
21. Kuno, K., and Matsushima, K. J. Biol. Chem.2001.273,13912-13917
22.. L.Y. Yao, C. Moody, E. Schonherr, T.N. Wight.Identification;of the proteoglycan versican in aorta and smooth muscle cells by DNA sequence analysis, in situ hybridization and immunohistochemistry, Matrix Biol.2004; 14:213-225.
23. A.D. Theocharis, I. Tsolakis, A. Hjerpe and N.K. Karamanos, Human abdominal aortic aneurysm is characterized by decreased versican concentration and specific downregulation of versican isoform V(0), Atherosclerosis.2002;154:367-376.
24. M.J. Merrilees, B. Beaumont and L.J. Scott, Comparison of deposits of versican, biglycan and decorin in saphenous vein and internal thoracic, radial and coronary arteries:correlation to patency, Coron Artery Dis 2007;12:7-16.
25. G.C. Jones and G.P. Riley, ADAMTS proteinases:a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis, Arthritis Res Ther.2005;7:160-169.
26.. Zimmermann DR, Lemire JM, Fischer JW.. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. JBiol Chem.2001; 276: 13372-13378.
27. John D. Sandy, Jennifer Westling, Richard D, Versican V1 Proteolysis in Human Aorta in Vivo Occurs at the Glu441-Ala442 Bond, a Site That Is Cleaved by Recombinant ADAMTS-1 and ADAMTS-4, J. Biol. Chem..2005;276:13372-13378,
28. Tortorella, M. D., Pratta, M., Liu, R. Q., Austin, J., Ross, O. H., Abbaszade, I., Burn, T., and Arner, E. J. Biol. Chem.2000.275,18566-18573
29. Tortorella, M. D., Liu, R.-Q., Burn, T., and Arner, E. Matrix Biol.2002;21: 499-511
30. Patwari, P., Kurz, B., Sandy, J. D., and Grodzinsky, A. J. Arch. Biochem. Biophys. 2000;374:79-85
31. Micky D. Tortorella, Elizabeth C. Arner, Robert Hills, α2-Macroglobulin Is a Novel Substrate for ADAMTS-4 and ADAMTS-5 and Represents an Endogenous Inhibitor of These Enzymes, J. Biol. Chem., Vol.2003;279:17554-17561,
32. Norata GD, Bjork H, Hanmsten A, Catapono AL, Eriksson P. High-density lipoprotein subfraction 3 decreases ADAMTS-1 expression induced by lipopolysaccharide and tumor necrosis factor-alpha in human endothelial cells. Matrix Biol.2004; 22:557-560
33. Z.S. and Khatri, J.J.,2002. Matrix metalloproteinases in vascular remodeling and atherogenesis:the good, the bad, and the ugly. Circ. Res.2002; 90:.251-262.
34. Basile DP, Fredrich K, Chelladurai B, Leonard EC. Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. Am J Physiol Renal Physiol.2008;294:928-36
35..L. Stevens Ph.D, C.A. Wheeler B.S., S.R. Tannenbaum Ph.D. Nitric oxide enhances aggrecan degradation by aggrecanase in response to TNF-but not IL-1β treatment at a post-transcriptional level in bovine cartilage explants.2008,;16: 489-497
36. Dick Wagsaterm, Hanna Bjork, Chaoyong Zhu,ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques,2008; 196:514-522
37. Eli Zamir and Benjamin Geiger, Molecular complexity and dynamics of cell-matrix adhesions, Journal of Cell Science 2001.114:3583-3590
38. Gakuji Hashimoto, Masayuki Shimoda, and Yasunori Okada,ADAMTS4 (Aggrecanase-1) Interaction with the C-terminal Domain of Fibronectin Inhibits Proteolysis of Aggrecan'J. Biol. Chem.,2005;279:32483-32491
39. Masahide Kashiwag, Micky Tortorella, Hideaki Nagase,TIMP-3 Is a Potent Inhibitor of Aggrecanase 1 (ADAM-TS4) and Aggrecanase 2 (ADAM-TS5) J. Biol. Chem..2007; 276:12501-12504.
40. Hashimoto, G., Aoki, T., Nakamura, H., Tanzawa, K., and Okada, Y Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1,2,3 and 4). FEBS Lett.2001;494:192-195
41. Llamazares, M., Cal, S., Quesada, V., and Lopez-Otin, C, ADAMTS4 (Aggrecanase-1) Interaction with the C-terminal Domain of Fibronectin Inhibits Proteolysis of Aggrecan J:Biol. Chem.2003;278:13382-1338.
42. Tontonoz, P., Nagy, L., Alvarez, J. G., Thomazy, V. A., and Evans, R. M. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998;93:241-252
43. Ricote, M., Huang, J., Fajas, L., Li, A., Welch, J., Najib, J., Witztum, J. L. Auwerx, J., Palinski, W., and Glass, C. K. Expression of the peroxisome proliferator-activated receptor γ(PPARγ) in human atherosclerosis and
regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Natl. Acad. Sci. U. S. A 1998;.95:7614-7619
44. Yamanishi, Y., Boyle, D. L., Clark, M., Maki, R. A., Tortorella, M. D., Arner, E. C., and Firestein, G. S. Expression and Regulation of Aggrecanase in Arthritis: The Role of TGF-β() J. Immunol.2002; 168:1405-1412
45. Lam JK, Chion CK, Zanardelli S. Further characterization of AD AMTS-13 inactivation by thrombin.. J Thromb Haemost.2007;5:1010-8.
46. Nadia Al-Fakhri, Jochen Wilhelm, Meinhard Hahn, Increased Expression of Disintegrin-Metalloproteinase ADAM-15 and ADAM-9 Following Upregulation of
47. Integrins a5b1 and avb3 in Atherosclerosis, Journal of Cellular Biochemistry.2003; 89:808-823
48. Vazquez, F., Hastings, G., Ortega, M. A., Lane, T. F. J. Biol. Chem.1999;274: 23349-23357
49. Kuno K, Terashima Y, Matsushima K. AD AMTS-1 is an active metalloprotease associated with the extracellular matrix. JBiol Chem.1999; 274:18821-18826
50. Molloy, S. S., Anderson, E. D., Jean, F., and Thomas, G.. Trends Cell Biol.1999; 9:28-35
51..S. Cal, A.J. Obaya, M. Llamazares, C. Garabaya, V. Quesada and C. Lopez-Otin, Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains, Gene.2002; 283:.49-62.
52. Gui Gao, Jennifer Westling, Vivian P, Activation of the Proteolytic Activity of ADAMTS4 (Aggrecanase-1) by C-terminal Truncation。J. Biol. Chem., 2007;277:11034-11041,
53. Flannery, C. R., Zeng, W., Corcoran, C., Collins-Racie, L. A., Chockalingam, P. S., Hebert, T., Mackie, S. A., McDonagh, T., Crawford, T. K., Tomkinson, K. N., LaVallie, E. R., and Morris, E. A..J. Biol. Chem.2002;277:42775-42780
54. Rodriguez-Manzaneque, J. C, Milchanowski, A. B., Dufour, E. K., Leduc, R., and Iruela-Arispe, M. L. (2000) J. Biol. Chem.275,33471-33479
55. Gao, G., Plaas, A., Thompson, V. P., Jin, S., Zuo, F., and Sandy, J. D. (2004) J. Biol. Chem.279,10042-10051
56. Yamanaka, H., Makino, K., Takizawa, M., Nakamura, H., Fujimoto, N., Moriya, H., Nemori, R., Sato, H., Seiki, M., and Okada, Y. Lab. Investig. 2000;80:677-687
57. Imai, K., Ohta, S., Matsumoto, T., Fujimoto, N., Sato, H., Seiki, M., and Okada, Y. () Am. J. Pathol.2004;151:245-256
58.Kashiwagi, M., Tortorella, M., Nagase, H., and Brew, K. J. Biol. Chem. 2001;276:12501-12504
59. Sandy JD, Westling J, Denegy RD, Iruela-Arispe ML, Verscharen C, Rodriguez-Mazaneque JC, Zimmermann DR, Lemire JM, Fischer JW, Wight TN, Clowes AW. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem.2001; 276:13372-13378
60. Ann-Cathrine Jonsson-Rylander; Tina Nilsson, Role of ADAMTS-1 in Atherosclerosis Remodeling of Carotid Artery, Immunohistochemistry, and Proteolysis of Versican, Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:180
61. S.P. Evanko, J.C. Angello and T.N. Wight, Formation of hyaluronan-and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells, Arterioscler Thromb Vasc Biol.2002;;19:1004-1013.
62. J.M. Lemire, K.R. Braun and P. Maurel et al, Versican/PG-M isoforms in vascular smooth muscle cells, Arterioscler Thromb Vasc Biol 2003;19:1630—1639
63. Izumi, Y., Hirata, M., Hasuwa, H., Iwamoto, R., Umata, T., Miyado, K., Tamai, Y., Kurisaki, T., Sehara-Fujisawa, A., Ohno, S., and Mekada, E. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J.1998 17,7260-7272
64. aab, G., and Klagsbrun, M. Heparin-binding EGF-like growth factor(1997) Biochim. Biophys. Acta 2003;1333:179-199
65. Fukuda, K., Kawata, S., Inui, Y., High Concentration of Glucose Increases Mitogenic Responsiveness to Heparin-Binding Epidermal Growth Factor-like Growth Factor in Rat Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol.2001;17,1962-1968
66. Herren, B., Raines, E. W., and Ross, R. Expression of a disintegrin-like protein in cultured human vascular cells and in vivo.FASEB J.1997;11,173-180
67. Canault M, Peiretti F, Kopp F, Bonardo B, Bonzi MF, Coudeyre JC, Alessi MC, Juhan-Vague I, Nalbone G. The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: possible contribution to elevated plasma levels of soluble TNF alpha receptors. Atherosclerosis.2005.
68. Hidetoshi SATOH, Motoyuki NAKAMURA, Mamoru SATOH,Expression and localization of tumour necrosis factor-and its converting enzyme in human abdominal aortic aneurysm, Clinical Science.2004 106,301-306
69. Matthias Canault, Franck Peiretti, Francis Kopp, The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice:Possible contribution to elevated plasma levels of soluble TNF alpha receptors, Atherosclerosis 2006; 187:82-91
70. P. Libby, P.M. Ridker and A. Maseri, Inflammation and atherosclerosis, Circulation.2002; 105:1135-1143.
71. P.R. Brauer, MMPs—role in cardiovascular development and disease, Front Biosci.2006;11:447-478.
72. C. Whatling, H. Bjork, S. Gredmark, A. Hamsten and P. Eriksson, Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes, J Lipid Res.2004;45:1768-1776.
73. J.D. Sandy, J. Westling and R.D. Kenagy et al., Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4, JBiol Chem.2001;276: 13372-13378.
74. R.D. Kenagy, A.H. Plaas and T.N. Wight, Versican degradation and vascular disease, Trends Cardiovasc Med 2006;16:209-215.
75. B. Bode-Lesniewska, M.T. Dours-Zimmermann and B.F. Odermatt et al, Distribution of the large aggregating proteoglycan versican in adult human tissues, J Histochem Cytochem 1996;44:303-312.
76. Perutelli P, Molinari AC, von Willebrand factor, von Willebrand factor-cleaving protease, and shear stress. Cardiovasc Hematol Agents Med Chem. 2007;5:305-10.
77.H. Langer, A.E. May, A. Bultmann and M. Gawaz, AD AM15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation, Thromb Haemost 2005;94:555-561
78. May AE, Kalsch T,Massberg S et al. Engagement of glycoprotein Ⅱb/Ⅲa (αⅡbβ3)on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 2002; 106:2111-7
79. Henn V,Slupsky JR,Grafe M et al.CD40 ligand on activated platelets triggers and inflammatory reaction of endothelial cells.Nature 1998;391:591-51
80. Heeshen C, Dimmeler S, Hamm CW et al. Soluble CD40 ligand in acute coronary syndromes.N Engl J Med 2003;348:1104-11
81. Chion CKNK, Doggen CJM, Crawley JTB,ADAMTS13 and von Willebrand factor and the risk of myocardial infarction in men. BLOOD.2007; 109:1998-2000.
82. Shunichiro Fuchigami, Koichi Kaikita, Kenji Soejima, Changes in plasma Von Willebrand factor-cleaving protease (ADAMTS13) levels in patients with unstable angina Thrombosis Research..2003; 23:432-439.
83. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol.1999; 10: 499-506.
84. Glover C, Ma X, Chen YX. Human in-stent restenosis tissue obtained by means of coronary atherectomy consists of an abundant proteoglycan matrix with a paucity of cell proliferation. Am Heart J.2002; 144:702-709.
85. Euan A. Ashley, MRCP, DPhil; Rossella Ferrara, MD; Network Analysis of Human In-Stent Restenosis. Circulation.2006; 114:2644-2654.
86. Richard D. Kenagy,Anna H. Plaas, and Thomas N. Wight, Versican Degradation and Vascular Disease, Trends in Cardiovascular Medicine.2006;16: 209-215
87. Evanko, S. P., Raines, E. W., Ross, R., Gold, LAm. J. Pathol.1998; 152,533-546
88. Kolodgie, F. D., Burke, A. P., Farb, A., Weber, D. K., Kutys, R.. Arterioscler. Thromb. Vasc. Biol.2002;22:1642-1648.
89._Peng-Sheng Zheng, Dana Vais, David LaPierre, PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation. Journal of Cell Science 2007;117:5887-5895
90. Almeida, E. A., Huovila, A. P., Sutherland, A. E., Stephens, L. E., Calarco, P. G., Shaw, L. M., Mercurio, A. M., Sonnenberg, A., Primakoff, P., Myles, D.G., and White, J. M. Cell.2000; 81:1095-1104
1. PS Zheng, D Vais and D Lapierre et al., PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation, J Cell Sci 2004; 117: 5887-5895
2. Wight,TN Wight and MJ Merrilees, Proteoglycans in atherosclerosis and restenosis:key roles for versican, Circ Res2004; 94:1158-1167.
3. Nikkari.ST Nikkari, HT Jarvelainen and TN Wight et al., Smooth muscle cell expression of extracellular matrix genes after arterial injury,
Am J Pathol.1994; 144:1348-1356
4. Finn, AV Finn, HK Gold and A Tang et al., A novel rat model of carotid artery stenting for the understanding of restenosis in metabolic diseases, J Vasc Res.2002; 39:414-425
5. Kenagy, RD Kenagy, JW Fischer and S Lara et al., Accumulation and loss of extracellular matrix during shear stress-mediated intimal growth and regression in baboon vascular grafts, J Histochem Cytochem.2005; 53:131-140.
6. Chung,IM Chung, HK Gold and SM Schwartz et al., Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment, J Am Coll Cardiol.2002; 40:2072-2081.
7. Farb, A Farb, FD Kolodgie and JY Hwang et al., Extracellular matrix changes in stented human coronary arteries, Circulation.2004; 110: 940-947.
8. Wight, TN Wight, S Lara and R Riessen et al., Selective deposits of versican in the extracellular matrix of restenotic lesions from human peripheral arteries, Am J Pathol1997; 151:963-973.
9. Matsuura,R Matsuura, N Isaka and K Imanaka-Yoshida et al., Deposition of PG-M/versican is a major cause of human coronary restenosis after percutaneous transluminal coronary angioplasty, J Pathol.1996; 180: 311-316.
10. Kolodgie,FD Kolodgie, AP Burke and TN Wight et al., The accumulation of specific types of proteoglycans in eroded plaques:a role in coronary thrombosis in the absence of rupture, Curr Opin Lipidol.2004; 15:575-582.
11. Ujita M, Shinomura T, Ito K, Kitagawa Y, Kimata K. Expression and binding activity of the carboxy-terminal portion of the core protein of PG-M, a large chondroitin sulfate proteoglycan. J Biol Chem. 2000:269:27603-27609.
12. Wight TN. The vascular extracellular matrix. In:Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. New York, NY:Raven Press; 1996:421-440
13. Yamagata M, Saga S, Kato M, Bernfield M, Kimata K. Selective distributions of proteoglycans and their ligands in pericellular matrix of cultured fibroblasts:implications for their roles in cell-substratum adhesion. J Cell Sci.2003;106:55-65.
14. Yamagata M, Suzuki S, Akiyama SK, Yamada KM, Kimata K. Regulation of cell-substrate adhesion by proteoglycans immobilized on extracellular substrates. J Biol Chem.1989:264:8012-8018.
15. Bode-Lesniewska, B., Dours-Zimmermann, M. T., Odermatt, B. F., Briner, J., Heitz, P. U., and Zimmermann, D. R. J. Histochem. Cytochem.2006; 44,303-312
16. Lemire, J. M., Braun, K. R., Maurel, P., Kaplan, E. D., Schwartz, S. M., and Wight, T. N. Arterioscler. Thromb. Vasc. Biol.2001; 19, 1630-1639
17. Yao, L. Y., Moody, C., Schonherr, E., Wight, T. N., and Sandell, L. J. Matrix Biol 1994:14,213-225
18. G Perides, RA Asher and MW Lark et al., Glial hyaluronate-binding protein:a product of metalloproteinase digestion of versican?, Biochem J 1995; 312:377-384.
19. A Passi, D Negrini and R Albertini et al., The sensitivity of versican from rabbit lung to gelatinase A (MMP-2) and B (MMP-9) and its involvement in the development of hydraulic lung edema, FEBS Lett 456 2005; 456:93-96.
20. Halpert et al.1996 I Halpert, UI Sires and JD Roby et al., Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme, Proc Natl Acad
Sci USA 1996:93:9748-9753.
21. Kenagy, RD Kenagy, JW Fischer and MG Davies et al., Increased plasmin and serine proteinase activity during flow-induced intimal atrophy in baboon PTFE grafts, Arterioscler Thromb Vasc Biol 2002; 22: 400-404
22. Sandy, JD Sandy, J Westling and RD Kenagy et al., Versican V1 proteolysis in human aorta in vivo occurs at the Glu445-Ala446 bond a site which is cleaved by recombinant ADAMTS-1 and ADAMTS-4, J Biol Chem 2001; 276:13372-13378
23. Jonsson-Rylander, AC Jonsson-Rylander, T Nilsson and R Fritsche-Danielson et al., Role of ADAMTS-1 in atherosclerosis: remodeling of carotid artery, immunohistochemistry, and proteolysis of versican, Arterioscler Thromb Vasc Biol 2005; 25:180-185.
24. Cross, NA Cross, S Chandrasekharan and N Jokonya et al., The expression and regulation of ADAMTS-1,-4,-5,-9, and-15, and TIMP-3 by TGFbetal in prostate cells:relevance to the accumulation of versican, Prostate.2005; 63:269-275
25. RP Somerville, JM Longpre and KA Jungers et al., Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1, J Biol Chem 2003; 278:9503-9513
26. AC Nicholson, SB Malik and JM Logsdon Jr et al., Functional evolution of ADAMTS genes:evidence from analyses of phylogeny and gene organization, BMC Evol Biol.2005; 5:11
27. MKester, P Waybill and M Kozak, New strategies to prevent restenosis, Am J Cardiovasc Drugs 1 2001; 12:77-83.
28. ST Nikkari, HT Jarvelainen and TN Wight et al., Smooth muscle cell expression of extracellular matrix genes after arterial injury, Am J Pathol 1994; 144:1348-1356
29. VK Nuthakki, PS Fleser and LE Malinzak et al., Lysyl oxidase expression in a rat model of arterial balloon injury, J Vasc Surg.2004; 40:123-129.
30. K Imanaka-Yoshida, R Matsuura and N Isaka et al., Serial extracellular matrix changes in neointimal lesions of human coronary artery after percutaneous transluminal coronary angioplasty:clinical significance of early tenascin-C expression, Virchows Arch Int J Pathol.2001; 439:185-190
31.31. R Matsuura, N Isaka and K Imanaka-Yoshida et al., Deposition of PG-M/versican is a major cause of human coronary restenosis after percutaneous transluminal coronary angioplasty, J Pathol.1996; 180: 311-316
32. RL Geary, ST Nikkari and WD Wagner et al., Wound healing:a paradigm for lumen narrowing after arterial reconstruction, J Vasc Surg.1998; 27:96-106
33. M Asakura, Y Ueda and S Nanto et al., Remodeling of in-stent neointima, which became thinner and transparent over 3 years—serial angiographic and angioscopic follow-up, Circulation.1998; 97: 2003-2006
34. B Langeveld, AJM Roks and RA Tio et al., Rat abdominal aorta stenting: a new and reliable small animal model for in-stent restenosis,J Vasc Res 2004; 41:377-386.
35. Peng-Sheng Zheng, Dana Vais, David LaPierre,et al. PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation Journal of Cell Science.2004;117: 5887-5895
36. aneurysmal abdominal aortas, BIOMEDICAL CHROMATOGRAPHY Biomed. Chromatogr.2003; 17:411-416
37. Toole BP, Wight TN, Tammi MI. Hyaluronan-cell interactions in cancer and vascular disease. J Biol Chem.2002; 277:4593-4596.
38. Bourin MC, Lindahl U. Glycosaminoglycans and the regulation of blood coagulation. Biochem J.1993; 289(pt 2):313-330.
39. Camejo G. The interaction of lipids and lipoproteins with the intercellular matrix of arterial tissue:its possible role in atherogenesis. Adv Lipid Res.1982; 19:1-53.
40. Radhakrishnamurthy B, Srinivasan SR, Vijayagopal P, Berenson GS. Arterial wall proteoglycans:biological properties related to pathogenesis of atherosclerosis. Eur Heart J.1990; 11 (suppl E): 148-157.
41. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol.1995; 15:551-561.
42. Kjellen L, Lindahl U. Proteoglycans:structures and interactions. Annu Rev Biochem.1991; 60:443-475
43. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis:the good, the bad, and the ugly. Circ Res.2002; 90:251-262.
44. Gutierrez P,O'Brien KD, Ferguson M, Nikkari ST, Alpers CE, Wight TN. Differences in the distribution of versican, decorin, and biglycan in atherosclerotic human coronary arteries. Cardiovasc Pathol.1997; 6:271-278.
45. Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek J, Virmani R. Coronary plaque erosion without rupture into a lipid core:a frequent cause of coronary thrombosis in sudden coronary death. Circulation. 1996; 93:1354-1363
46. IP Hayward and GR Campbell et al., Relationship of glycosaminoglycan and matrix changes to vascular smooth muscle cell phenotype modulation in rabbit arteries after acute injury,J Vasc Surg 2001; 33:155-164.
47. S Inoue, H Koyama and T Miyata et al., Pathogenetic heterogeneity of in-stent lesion formation in human peripheral arterial disease, J Vasc Surg 2002; 35:672-678.
48. SA Berceli, MG Davies and RD Kenagy et al., Flow-induced neointimal regression in baboon polytetrafluoroethylene grafts is associated with decreased cell proliferation and increased apoptosis,J Vasc Surg 2002; 36:1248-1255
49. EJR Mattsson, TR Kohler and SM Vergel et al., Increased blood flow induces regression of intimal hyperplasia, Arterioscler Thromb Vasc Biol 2007; 17:2245-2249
50. EC Arner, Aggrecanase-mediated cartilage degradation, Curr Opin Pharmacol 2002; 2:322-329
51. W Sheng, GZ Wang and YL Wang et al., The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis, Mol Biol Cell.2005; 16:1330-1340
52. Y Zhang, L Cao and C Kiani et al., Promotion of chondrocyte proliferation by versican mediated by G1 domain and EGF-like motifs, J Cell Biochem.1999; 73:445-457
53. Huang, MJ Merrilees and K Braun et al., Inhibition of versican synthesis by antisense alters smooth muscle cell phenotype and induces elastic fiber formation in vitro and in neointima after vessel injury, Circ Res.2006; 98:370-377
54. SP Evanko, JC Angello and TN Wight, Formation of hyaluronan-and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells, Arterioscler Thromb Vasc Biol.2001;19:1004-1013
55. RT Matthews, SC Gary and C Zerillo et al., Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member, J Biol Chem.2000;275:22695-22703
56. M Formato, M Farina and R Spirito et al., Evidence for a
proinflammatory and proteolytic environment in plaques from endarterectomy segments of human carotid arteries, Arterioscler Thromb Vasc Biol.2003; 24:129-135.
57. Y Zhang, L Cao and BL Yang et al., The G3 domain of versican enhances cell proliferation via epidermal growth factor-like motifs, J Biol Chem 2002; 273:21342-21351
58. PS Zheng, J Wen and LC Ang et al., Versican/PG-M G3 domain promotes tumor growth and angiogenesis, FASEB J. (2004; 18:754-756
59. Y Wu, Y Zhang and L Cao et al., Identification of the motif in versican G3 domain that plays a dominant-negative effect on astrocytoma cell proliferation through inhibiting versican secretion and binding, J Biol Chem.2001; 276:14178-14186.
60. BL Yang, Y Zhang and L Cao et al., Cell adhesion and proliferation mediated through the G1 domain of versican, J Cell Biochem.2003; 72: 210-220
61. Al Olin, M Morgelin and T Sasaki et al., The proteoglycans aggrecan and versican form networks with fibulin-2 through their lectin domain binding, J Biol Chem.2001;276:1253-1261.
62. MJ Merrilees, JM Lemire and JW Fischer et al., Retrovirally mediated overexpression of versican V3 by arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointima after vascular injury, Circ Res.2002;90:481-487.
63. JM Lemire, MJ Merrilees and KR Braun et al., Overexpression of the V3 variant of versican alters arterial smooth muscle cell adhesion, migration, and proliferation in vitro, J Cell Physiol.2002;90: 38-45.
64. J Hirose, H Kawashima and 0 Yoshie et al., Versican interacts with chemokines and modulates cellular responses, J Biol Chem.2001;276: 5228-5234
65. H Kawashima, K Atarashi and M Hirose et al., Oversulfated chondroitin/dermatan sulfates containing GlcAbetal/IdoAalphal-3GalNAc (4,6-0-disulfate) interact with L-and P-selectin and chemokines, J Biol Chem.2002;277:12921-12930.
66. M McGee and WD Wagner, Chondroitin sulfate anticoagulant activity is linked to water transfer:relevance to proteoglycan structure in atherosclerosis, Arterioscler Thromb Vasc Biol.2003;23:1921-1927.
67. E Di Cera, Atherosclerosis:testing the water, Arterioscler Thromb Vasc Biol.2003; 23:1713-1714
68.. M Kato, HM Wang and V Kainulainen et al., Physiological degradation converts the soluble syndecan-1 ectodomain from an inhibitor to a potent activator of FGF-2, Nat Med.2004;4:691-697.
69. AB Csoka, GI Frost and R Stern, The six hyaluronidase-like genes in the human and mouse genomes, Matrix Biol 2001:20:499-508.
70. AC Jonsson-Rylander, T Nilsson and R Fritsche-Danielson et al., Role of ADAMTS-1 in atherosclerosis:remodeling of carotid artery, immunohistochemistry, and proteolysis of versican, Arterioscler Thromb Vasc Biol.2005;25:180-185.