摘要
目前,动脉粥样硬化(AS)易损斑块在导致急性心血管事件方面的重要性已受广泛重视。改善易损斑块内部成分,使其趋于稳定,成为防治急性心血管事件的重要内容。随着“AS炎症反应”学说的公认,为中医产生新的冠心病病机学说、更新治疗观念提供了良好契机。我们在既往动物实验研究的基础上,提出“活血解毒——抑制炎症反应——稳定斑块”的假说,并从基础研究和临床试验两个方面展开研究。
1.基础研究:活血解毒中药对ApoE基因敲除(ApoE~(-/-))小鼠斑块稳定性的影响及机制探讨。
目的:观察活血(三七总皂苷)、解毒(黄连提取物)、活血解毒(虎杖提取物、大黄醇提物)中药有效部位对ApoE~(-/-)小鼠主动脉粥样斑块稳定性的影响,并从抑制炎症反应、调节脂质代谢和改善胶原沉积及代谢三个角度探讨其作用机制。
方法:70只ApoE~(-/-)小鼠经“西方膳食”饲料喂养13周后,随机取4只小鼠观察基础AS病变水平。其余小鼠随机分为6组:虎杖提取物组、大黄醇提物组、黄连提取物组、三七总皂苷组、辛伐他汀组、模型组各11只,并以同品系C57BL/6J小鼠10只作为正常对照。继续高脂喂养并按体重比折算的临床推荐剂量给予相应药物治疗13周后,处死取主动脉根部的4个切面,分别行HE染色、Movat染色、苦味酸天狼星红染色以及免疫组织化学染色法观察斑块内部成分,同时取血清用酶联免疫吸附法(ELISA)检测炎性相关指标,实时荧光定量PCR法检测小鼠主动脉内相关基因表达,观察并计算:1)主动脉斑块形态变化:包括斑块面积,细胞外脂质、泡沫细胞、胶原成分各自占斑块面积的百分比以及斑块内脂质成分与胶原成分比值,埋藏纤维帽数目以及纤维帽占斑块表层比值,并结合免疫组化染色半定量观察斑块内平滑肌细胞的阳性面积,最后采用易损指数综合评价药物对小鼠主动脉斑块稳定性的影响;2)血脂改变及对脂质代谢相关基因周脂素和清道夫受体CD36的基因表达影响;3)炎性指标:血清超敏C反应蛋白(hs-CRP)和可溶性白细胞分化抗原配体(sCD40L)水平、斑块内粒细胞-巨噬细胞集落细胞刺激因子(GM-CSF)和肿瘤坏死因子α(TNF-α)的表达、过氧化物酶体增殖物激活受体γ(PPAR-γ)和核转录因子-κB(NF-κB)的基因表达;4)胶原的合成代谢:Ⅰ、Ⅲ型胶原的组成、基质金属蛋白酶9(MMP-9)及组织金属蛋白酶抑制剂1(TIMP-1)的表达。
结果:(1)无论是在改善斑块易损指数方面,还是在修复斑块纤维帽的能力方面,活血解毒中药虎杖提取物及大黄醇提物组,均优于单纯活血中药三七总皂苷和单纯解毒中药黄连提取物组。综合评价药物稳定斑块的作用,上述药物表现出的趋势是活血解毒中药＞清热解毒中药＞活血化瘀中药;(2)虎杖提取物和大黄醇提物还可明显降低ApoE~(-/-)小鼠血清炎症标志物hsCRP及sCD40L水平,优于活血对照药三七总皂苷和解毒对照药黄连提取物,这与稳定斑块的作用相平行。各中药组对斑块内炎性因子GM-CSF表达均有一定抑制作用,大黄醇提物还可明显抑制TNF-α表达,而黄连提取物组则明显促进斑块内PPAR-γmRNA和蛋白表达;(3)各中药组可不同程度调节ApoE~(-/-)小鼠血清脂蛋白水平,减少斑块内细胞外脂质成分,其中大黄醇提物、黄连提取物还可明显抑制斑块内perilipin mRNA表达,但各中药组清道夫受体CD36的基因表达无显著影响;(4)各中药组均可明显增加斑块内胶原纤维成分,降低Ⅲ/Ⅰ型胶原比值,其中虎杖提取物、三七总皂苷、黄连提取物组MMP-9/TIMP-1比值亦明显降低。
结论:活血、解毒及活血解毒中药有效部位三七总皂苷、黄连提取物、虎杖提取物、大黄醇提物在临床推荐剂量上均可通过改善斑块内部成分发挥稳定易损斑块的作用,但其作用环节有所差异。其中,兼有活血和解毒作用的中药虎杖提取物、大黄醇提物效果最为显著。其机制可能与抑制炎症反应、调节脂质代谢和改善胶原沉积及代谢有关,尤以抑制炎症反应为最主要机制,验证了“活血解毒——抑制炎症反应——稳定斑块”的假说。
2.临床研究:活血解毒中药对冠心病稳定期患者血清炎症标记物的影响。
目的:以新清宁片(熟大黄)为活血解毒中药的代表药物、以丹七片为活血对照药,观察在常规他汀类药物治疗基础上加用新清宁或丹七片对冠心病稳定期患者血清炎症标志物的影响。
方法:将30例冠心病稳定期患者随机分为三组:他汀对照组,予他汀类降脂药常规治疗;活血中药治疗组,在他汀类药物常规治疗基础上加用丹七片,每次三片(0.3g╱片),每天3次;活血解毒中药治疗组,在他汀类药物常规治疗基础上加用新清宁片,每次三片(0.3g╱片),每天3次。每组10例。治疗1个月后,观察患者治疗前后血清hs-CRP、TNF-α、MMP-9和CD40L浓度变化,血脂水平,心绞痛症状和血瘀证积分变化。
结果:无论是降低冠心病患者血清hs-CRP浓度、调节血脂还是降低患者心绞痛症状和血瘀证积分方面,活血解毒中药治疗组(他汀药常规治疗加用新清宁片)均表现出良好作用,优于他汀药对照组及活血中药治疗组(他汀药常规治疗加丹七片)。但各组对血清TNF-α、MMP-9和CD40L水平影响无显著差异。
结论:对于稳定期冠心病患者,他汀药常规治疗加用活血解毒中药在抗炎、调脂等方面优于加用活血中药,与实验研究结果一致,为“活血解毒——抑制炎症反应——稳定斑块”的假说提供了进一步支持。虽然在改善心绞痛症状和血瘀证积分方面,加用活血解毒药亦比加用活血中药作用明显,但本研究仅为小样本预试验,在急性心血管事件预防方面有无更大获益尚需大样本、长期随访的临床试验加以证实。
Nowadays,vulnerable atherosclerotic plaque(VAP) has been highlighted for its role in leading to acute cardiovascular events.Thus,it is regarded as an important strategy to prevent the incidence of acute cardiovascular events by changing the composition of VAP to make it more stable.The theory of inflammation reaction in atherosclerosis(AS) provides innovation of pathogenesis theory and refreshment of therapeutic concept on coronary heart disease(CHD) in view of traditional Chinese medicine(TCM) with a good opportunity.Based on the results of our previous experiment study,we proposed a hypothesis that the method of activating blood circulation and detoxicating(ABCD) could stabilize atherosclerotic plaque by inhibiting inflammatory reaction,and try to confirm it in the following experimental research and clinical study.
1.Experimental research:Study on the effect and underlying mechanism of herbs with function of activating blood circulation(ABC),detoxicating(D) as well as ABCD on plaque stability of ApoE gene-knockout(ApoE~(-/-)) mice.
Objective:To observe the effects of herbal extractives with function of ABC (saponins of Panax pseudo-ginseng,SPP),D(Coptis chinensis extractive,CCE) and ABCD(giant knotweed rhizome,GKR;rhubarb extractives,RE) on the stability of VAP in the aortic roots of fat-fed ApoE~(-/-) mice and investigate the mechanisms in views of inhibiting inflammatory reaction,modulating lipid metabolism and improving collagen deposition and metabolism.
Methods:Seventy ApoE~(-/-) mice were fed a high-fat diet for 13 weeks until the mature atherosclerotic plaques formed.Thereafter,they were randomized to six groups(11 in each group) and fed a high-fat diet for subsequent 13 weeks:GKR group,RE group, CCE group,SPP group,simvastatin group(positive control),and control group.Moreover, another 10 mice(C57BL/6J) was served as a normal control group.The drug-treated groups were medicated with respective drug in a clinically relevant dose for another 13 weeks.Then all the mice were sacrificed at the end of experiment.Their blood was collected for determination of blood lipids and inflammatory indices by Enzyme-Linked Immuno Srbent Assay.The morphology and composition of atherosclerotic plaques in four sections of aortic roots treated with Movat stain,HE stain and Sirius red picro-polarization method and immunohistochemistry stain respectively.The related gene expressions in the aorta of mice were determined by real-time fluorescent quantitative PCR technology.The indices includes:1) The morphology and composition of atherosclerotic plaques in aortic roots:plaque area,the percentage of extracelluar lipids,foam cells and collagen in plaque, the ratio of lipid to collagen content in plaque,the number of buried fibrous caps and the ratio of the length of fibrous cap to plaque intima.The effect on plaque stability was evaluated by using the vulnerability index(area of foam cells and extracellular lipids/area of collagens and smooth muscle cells);2) The blood lipids level and the gene expressions of perilipin and scavenger receptor CD36 associated with lipid metabolism;3 ) Inflammatory indices:serum high-sensitivity C reaction protein(hs-CRP) and soluble leukocyte differentiation Ag-40 ligand(sCD40L),the expressions of granulocyte-macrophage colony-stimulating factor(GM-CSF) and tumor necrosis factor-alpha (TNF-a),the gene expressions of peroxisome proliferator-activated receptor-γ(PPAR-γ) and nuclear factor-kappa B(NF-KB).4) Collagen metabolism:the ratio of collagenⅢtoⅠin plaque,the protein expressions of matrix metalloprotease-9(MMP-9) and tissue inhibitor-1 of metalloproteinases(TIMP-1).
Results:(1) The herbal extractives with the effect of ABCD(GKR and RE) were significantly superior to ABC group(SPP) and D group(CCE) not only in improving the vulnerability index in plaque,but also in the capability of restoring fibrous cap.The comprehensive effects of the above herbs was manifested as a trend:ABCD＞D＞ABC. (2) Compared with ABC and D group,the concentrations of hsCRP and sCD40L in serum were significantly decreased in ABCD group treated with either GKR or RE,which is parallel to their effects on stabilizing atherosclerotic plaque.All of the above herbs could inhibit the expressions of GM-CSF in plaque.RE also significantly inhibited the protein expression of TNF-a,while CCE could significantly promote the mRNA and protein expression of PPAR-γ.(3) The above herbs could modulate serum lipid level to different degree and diminish extracellular lipids content in plaque.RE and CCE also remarkably inhibit the gene expression of perilipin.However,none of the above herbs showed effect on the gene expression of scavenger receptor CD36;(4) All of the above herbs could significantly increase collagen contents in plaque and reduce the ratio of collagenⅢ/Ⅰ, GKR,SPP and CCE could also reduce the ratio of MMP-9 to TIMP-1.
Conclusions:The herbal extractives with function of ABC(SPP),D(CCE) and ABCD(GKR and RE) could stabilize VAP by changing plaque composition in clinically relevant doses with different mechanisms of action.The herbal extractives with function of ABCD(GKR and RE) showed superior effect on stabilizing VAP and the mechanisms of action might be related to inhibiting inflammatory reaction,modulating lipids metabolism and improving collagen deposition and metabolism.The inhibition of inflammatory reaction as the major mechanism also verified our hypothesis.
2.Clinical study:The effects of the herbs with function of ABCD on the serum inflammatory markers in stable CHD patients.
Objective:To observe the additional effects of Xin Qing-ning Tablets,(a representative herb with the effect of ABCD,consisting of RE),or Dan Qi Tablets(as a control with the effect of ABC,consisting of Salvia miltiorrhiza and Panax pseudo-ginseng) on the serum inflammatory markers in stable CHD patients receiving standardized statins treatment.
Methods:Thirty stable CHD patients were randomized to three groups(10 in each group):the control group treated with standardized statins;the ABC group,treated with Dan Qi Tablets in addition to standardized statins treatment;the ABCD group,treated with Xin Qing-ning Tablets based on standardized statins treatment.After one month treatment, the concentrations of hs-CRP、TNF-a、MMP-9 and CD40L in serum of CHD patients before and after treatment were determined.Moreover,the blood lipids level,the scores of angina pectoris and blood stasis syndrome were also examined.
Results:The ABCD group showed better effects in reducing the concentration of hs-CRP in serum,modulating blood lipid level,and improving the scores of angina pectoris and blood stasis syndrome,as compared with the control group and the ABC group.As for the concentrations of TNF-a、MMP-9 and CD40L in serum,there were no significant difference among groups.
Conclusions:For stable CHD patients,the treatment with the herb with function of ABCD was superior to the treatment with function of ABC based on stabdardized statins treatment in both inhibiting inflammatory reaction and modulating blood lipids,which is consistent with our experimental results.The results also showed the better effect of ABCD group on improving the scores of angina pectoris and blood stasis syndrome as compared to ABC group.However,this is only a small-sample pilot study,whether the herbs with function of ABCD has additional benefit on preventing acute cardiovascular events still needs further demonstration with a large-scale and long-term follow-up clinical trial.
引文
[1]Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definition and risk assessment strategies:part Ⅰ[J].Circulation.2003,108(14):1664-1672.
[2]Ambrose JA,Eulogio EM.A new paradigm for plaque stabilization[J].Circulation.2002,105(16):2000-2004.
[3]文川,徐浩,黄启福,等.活血中药对ApoE缺陷小鼠血脂及AS斑块炎症反应的影响[J].中国中西医结合杂志,2005,25(4):345-348.
[4]文川,徐浩,黄启福,等.几种活血中药对ApoE缺陷小鼠AS斑块的影响[J].中国病理生理杂志,2005,21(5):864-867.
[5]Johnson J,Carson K,Williams H,et al.Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse:model characterization and effects of pravastatin treatment[J].Circulation,2005,111(23):1422-1430.
[6]许淑云,卞如濂,陈修.药理实验方法学[M].第3版.北京:人民卫生出版社,2002:202-204.
[7]Suzuki H,Kurihara Y,Takeya M,et al.A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection[J].Nature.1997,386(6622):292-296.
[8]李莉,翟同均,陈融等.Movat五色套染法的改进及应用[J].临床与实验病理学杂志,2002,18(6):660-662.
[9]Masashi S,Takashi I,Yasuhiko H,et al.Fibromuscular cap composition is important for the stability of established atherosclerotic plaques in mature WHHL rabbits treated with sstatins[J].Atherosclerosis,2001,157(1):75-84.
[10]Johnson JL,Fritsche DR,Behrendt M,et al.Effect of broadspectrum matrix metalloproteinase inhibition on athero sclerotic plaque stability[J].Cardiovasc Res. 2006,71(4):586-595.
[11]王利津,徐强.黄连解毒汤的抗炎作用机理研究[J].中国中药杂志,2000,25(8):493-496.
[12]Ross R.Atherosclerosis:an inflammatory disease[J].N Engl J Med.1999,340(2):115-126.
[13]徐浩,陈可冀.冠心病易损斑块与中西医结合干预的实践与思考[J].中西医结合心脑血管病杂志 2006,4(11):941-942.
[14]沈阳辉,朱鹏立.白藜芦醇在AS中抗炎作用机制探讨[J].国外医学·老年医学分册,2006,27(4):169-172.
[15]Chang CH,Lin CC,Yang JJ.Anti-inflammatory effects of emodin from ventilago leiocarpa[J].Am.J.Chin.Med.1996,24(2):139-142.
[16]Hei ZQ,Huang HQ,Tan HM.Emodin inhibits dietary induced atherosclerosis by antioxidation and regulation of the sphingomyelin pathway in rabbits[J].Chin.Med.J.2006,119(10):868-870.
[17]Jing Y,Yang J,Wang Y,et al.Alteration of subcelluar redox equilibrium and the consequent oxidative modification of nuclear factor kappaB are critical for anticancer cytotoxicity by emodin,a reactive oxygen species-producing agent[J].Free Radic.Biol,2006,40:2183-2197.
[18]彭旷,杨永宗.载脂蛋白E及其基因敲除小鼠的研究进展[J].心血管病学进展,2006,28(1):82-85.
[19]Mann J,Davies MJ.Mechanisms of progress in native coronary artery disease:role of healed plaque disruption[J].Heart,1999,82(9):265-268.
[20]Burke AP,Kolodgie FD,Farb A,et al.Healed plaque ruptures and sudden coronary death[J].Circulation.2001,103(5):934-940.
[21]Varvana AM,Mills PG,Davies MJ.Relationship between coronary artery remodeling and plaque vulnerability[J].Circulation.2002,105(3):939-943.
[22] Schoenhagen P, Ziada KM, Vince DG, et al. Arterial remodeling and coronary diseases: the concept of "dilated" and "obstructive" coronary atherosclerosis[J]. J AM Coll Cardiol. 2001, 38(7):297-306.
[23] Birgelen CV, K Linkhart W, Mintz G S, et al.Plaque distribution and vascular remodeling of ruptured and non-ruptured coronary plaques in the same vessel: an intravascular ultrascound study in vivo[J]. J AM Coll Cardiol. 2001, 37(6):1864-1870.
[1]Zhu J,Quyyumi AA,Norman JE,et al.The possible role of hepatitisA virus in the pathogenesisof atherosclerosis[J].J Infect Dis.2000,182(5):1583-1587.
[2]Renu V,Jagat N,Martin BL.The vulnerable atherosclerotic plaque:strategies for diagnosisand management[J].2007,395(6):97.
[3]Rupprecht H J,Blankenberg S,Bickel C,et al.Impact of viral and bacterial infectious burden on long term prognosis in patients with coronary artery disease[J].Circulation.2001,104(1):25-31.
[4]杨永宗.动脉粥样硬化性心血管病基础与临床[M].北京,科学出版社,2004:101-102.
[5]王卫明.C反应蛋白的研究进展[J].心血管病学进展,2005,26(1):73.
[6]史文元,唐朝克,杨永宗.CD40-CD40L与斑块的不稳定性[J].生命的化学,2004,24(3):224-226.
[7]Goran KH.Inflammation,atherosclerosis,and coronary artery disease[J].N Engl J Med,2005,352(16):1685-1695.
[8]Seshiah PN,Kereiakes DJ,Vasudevan SS,et al.Activated monocytes induce smooth muscle cell death:role of macrophage colony-stimulating factor and cell contact[J].Circulation.2002,105(2):174-180.
[9]文川,徐浩,黄启福,等.活血中药对ApoE缺陷小鼠血脂及AS斑块炎症反应的影响[J].中国中西医结合杂志,2005,25(4):345-348.
[10]Joseph JB,Peter LW,Martin RB.Tumor necrosis factor-a promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms[J].Arterioscler Thromb Vasc Biol,2003,23:1553-1558.
[11]Jiang C,Ting AT,Seed B.PPAR γ agonists inhibit production of monocyte inflammatory cytokines[J].Nature,1998,391(6662):82-86.
[12]徐宝华,赵慧颖.AS不稳定斑块的研究进展[J].心血管病学进展,2005,26(5):498-501.
[13]付晓春,王敏伟.黄连解毒汤的抗血栓作用研究[J].沈阳药科大学学报,2001,18(6):425.
[14]杜艳芝,闫晓梅,胡维诚,等.清热解毒液对高脂血症大鼠内皮素影响的研究[J].中国病理生理杂志,1999,15(12):1344.
[15]朱平,张学霞.清热解毒方对血管内皮细胞增殖的影响[J].山西中医,2003,19(5):41.
[16]周明学,徐浩.过氧化物酶体增殖物激活受体γ与易损斑块关系的研究进展[J].心血管病学进展,2007,28(4):610-612.
[1]Tailleux A,Duriez P,Fruchart JC,et al.Apolipoprotein A Ⅱ,HDL metabolism and atherosclerosis[J].Atherosclerosis,2002,164(1):1-13.
[2]Nissen SE,Tuzcu EM,Schoenhagen P,et al.Effect of intensive compared with moderate lipid-lowering therapy on progression coronary atherosclerosis:a randomized controlled trial[J].J Am Med Assoc,2004,291(9):1071-1080.
[3]Mavab M,Anantharamaiah GM,Reddy ST,et al.Mechanisms of disease:proatherogenic HDL-an evolving field[J].Nar Clin Pract Endocrino Metab,2006,2(9):504-511.
[4]Bittner V,Hardison R,Kelsey SF,et al.Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass Angioplasty Revascularization Investigation(BARI)[J].Circulation.2002,106(20):2537-2542.
[5]王东琦,王归真,李云萍,等.单项血脂和血脂比值与冠状动脉病变严重程度的相关性(J).西安交通大学学报(医学版),2007,25(3):124-126.
[6]Fabien F,Liliana L,Guiletta C,et al.Overexpression of Perilipin and Genes Promoting Cholesterol Storage and Repression of ABCA1 Expression[J].Arterioscler Thromb Vasc Biol.2005,25(5):1711-1717.
[7]Faber BC,Cleutjens KB,Niessen RL,et al.Identification of genes potentially involved in rupture of human atherosclerotic plaques[J].Circ Res.2001,89(6):547-554.
[8]Shimizu M,Takeshita A,Tsukamoto T,et al.Tissue selective,bidirectional regulation of PEX11 alpha and perilipin genes through a common peroxisome proliferator response element[J].Mol Cell Biol.2004,24(4):1313-1323.
[9]Nagai S,Shimizu C,Umetsu M,et al.Identification of afunctional peroxisome proliferator activated receptor or responsive element with in themurine perilipin gene.Endocrinology[J].2004,145(5):2346-2356.
[10]Arimura N,Horiba T,Imagawa M,et al.The peroxisome proliferator activated receptor gamma regulaties expression of the perilipin gene in adipocytes[J].J Biol Chem,2004,279(8):10070-10076.
[11]Dalen KT,Schoonjans K,Ulven SM,et al.Adipose tissue expression of the lipid droplet associating proteins S312 and perilipin is controlled by peroxisome proliferator activated receptor gamma[J].Diabetes,2004,53(3):1243-1252.
[12]Hart J,Hajjar DP,Tauras JM,et al.Cellular cholesterol regulates expression of the macrophage type B scavenger receptor,CD36[J].J Lipid Res,1999,40(5):830-838.
[13]刘浩,刘秉文.动脉壁脂蛋白受体与AS[J].中国动脉硬化杂志,2002,10(2):171-174.
[1]Yu WH,Yu S,Meng Q,et al.TIMP binds to sulfated glycosaminoglycans of the extracellularmatrix[J].J Biol Chem.2000,275(31):226-232.
[2]黎小间,雷涛,高建华,等.苦味酸-天狼星红偏振光法检测增生性瘢痕组织胶原[J].第一军医大学学报,2002,22(3):217-219.
[3]王伯沄.病理学技术[M].第1版.人民卫生出版社.2000,280.
[4]陈倩,吴宗贵.胶原与粥样斑块稳定性的关系[J].国外医学·心血管病分册,2001,28(3):144-146.
[5]Gough P.J,Gomez,I.G.,Wille,P.T,et al.Macrophage expression of active MMP-9induces acute plaque disruption in ApoE-deficient mice[J].J Clin Invest.2006,116(1):59-69.
[6]Blankenberg,S,Rupprecht,H.J,Poirier,O,et al..Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease[J].Circulation.2003,107(2):1579-1585.
[7]Fukuda,D,Shimada,K,Tanaka,A,et al.Comparison of levels of serum matrix metalloproteinase-9 in patients with acute myocardial infarction versus unstable angina pectoris versus stable angina pectoris[J].Am.J.Cardiol.2006,97(2):175-180.
[8]Marc F,Mark S,Martin G,et al.Matrix Metallproteinases in Cerebrovascular Diseases[J].Cerebrovascular Diseases,2005,20(6):141-151.
[9]刘金来,关良劲,谢旭晶,等.急性冠状动脉综合征患者血浆基质金属蛋白酶及其抑制因子的变化[J].中国病理生理杂志,2004,20(10):1921-1922.
[10]杨永宗.AS性心血管病基础与临床[M].北京,科学出版社,2004,581.
[11]周明学,徐浩.过氧化物酶体增殖物激活受体γ与易损斑块关系的研究进展[J].心血管病学进展,2007,28(4):610-612.
[1]文川,徐浩,黄启福,等.活血中药对ApoE缺陷小鼠血脂及AS斑块炎症反应的影响[J].中国中西医结合杂志 2005;25(4):345-348.
[2]文川,徐浩,黄启福,等.几种活血中药对ApoE缺陷小鼠AS斑块的影响[J].中国病理生理杂志2005:21(5):864-867.
[3]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠血脂和AS斑块炎症反应的影响[J].中国中西医结合杂志.2008,28(2):126-130.
[4]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠AS 斑块炎症反应的影响[J].中西医结合心脑血管病杂志,2007,5(12):1202-1205.
[5]中国中西医结合学会活血化瘀专业委员会.血瘀证诊断标准.中国中西医结合杂志,1987,7(3):129.
[6]王阶.血瘀证诊断标准的研究.活血化瘀研究与临床[M].北京医科大学中国协和医科大学联合出版社.第1版.1993:7.
[7]Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definitionsand risk assessment strategies:part Ⅰ[J].Circulation,2003,108:1664-1672.
[8]王卫明.C反应蛋白的研究进展[J].心血管病学进展,2005,26(1):73.
[9]Libby P,Aikawa,M.Stabilization of atherosclerotic plaques:new mechanisms and clinical targets[J].Nat.Med,2002,8:1257-1262.
[10]Marc F,Mark S,Martin G,et al.Matrix Metallproteinases in Cerebrovascular Diseases[J].Cerebrovascular Diseases,2005,20:141-151.
[11]Fukuda,D,Shimada,K,Tanaka,A,et al.Comparison of levels of serum matrix metalloproteinase-9 in patients with acute myocardial infarction versus unstable angina pectoris versus stable angina pectoris[J].Am.J.Cardiol.2006,97,175-180.
[12]龚澄.新清宁片治疗高脂血症的临床研究[J].现代中西医结合杂志,2001,10(7):1219-1220.
[13]牟元心.新清宁片治疗高脂血症34例临床观察[J].临床荟萃,1995,10(21):1000.
[14]Mavab M,Anantharamaiah GM,Reddy ST,et al.Mechanisms of disease:proatherogenic HDL-an evolving field[J].Nar Clin Pract Endocrino Metab,2006,2(9):504-511.
[1]Falk E,Shah PK,Fuster V.Coronary plaque disruption[J].Circulation,1995,92(3):657-671.
[2]Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definitionsand risk assessment strategies:part Ⅰ[J].Circulation,2003,108(15):1664-1672.
[3]Smits PC,Pasterkarnp GJaegere PP,et al.Angioscopic complex lesions are predominantly compensatory enlarged:an angioscopy and intracoronary ultrasound study[J].Cardiovasc Res,2003,41:458-464.
[4]Moreno PR,Corti R,Fuster V.Understanding atherothrombosis:from vulnerable plaque to vulnerable patient[J].International Congress Series,2004,1262(5):39-44.
[5]Renu V,Jagat N,Martin BL.The vulnerable atherosclerotic plaque:strategies for diagnosisand management[J].2007,395:97.
[6]Zaman AG,Helft G,Worthley SG,et al.The role of plaque rupture and thrombosis in coronary artery disease[J].Atherosclerosis,2006,149(2):251-266.
[7]Buffon A,Biasucci LM,Liuzzo G,et al.Widespread coronary inflammation in unstable angina[J].N Engl J Med,2002,347(1):5-12.
[8]周明学,徐浩.浅谈从“人易患的病”到“易患病的人”治疗思路的演变[J].中华中医药学刊,2006,24(12):2213-2215。
[9]王涛,浦艳华,殷洁.易损斑块与急性冠脉综合征[J].心血管病学进展,2007,28:286-288.
[10]李崇剑,高润霖,杨跃进,等.易损斑块的病理生理机制及其检测的研究进展[J].中华心血管病杂志,2004,32(6):570-573.
[11]Blake GJ,Ridker PM.C-reactive protein and other inflammatory risk markers in acute coronary syndromes[J].J Am Coll Cardiol,2003,41(4 Suppl S):S37-42.
[12]Pearson TA,Mensah GA,Alexander RW,et al.Markers of inflammation and cardiovascular disease,application to clinical and public health practice.a statement of healthcare professionals from the centers for disease control and prevention and the American Heart Association[J].Circulation,2003,107:499
[13]Lee WH,Lee Y,Kim JR et al.Activation of monocytes,T lymphocytes and plasma inflammatory inarkers in angina patients[J].EXP Mol Med,1999,31(3):159-164.
[14]牛玉宏,许从峰,史剑慧,等.感染负荷与粥样硬化形成及斑块性质的相关性[J].中华心血管病杂志,2005,33(4):303-306.
[15]杨永宗.动脉粥样硬化性心血管病基础与临床[M].北京,科学出版社,2004:101-102.
[16]Armstrong EJ,Morrow DA,Sabatine MS.Inflammatory biomarkers in acute coronary syndromes:part Ⅳ:matrix metalloproteinases and biomarkers of platelet activation[J].Circulation,2006,113(23):382-385.
[17]Goran KH.Inflammation,Atherosclerosis,and Coronary Artery Disease[J].N Engl J Med,2005,352(16):1685-1695.
[18]Kolodgie FD,Narula J,Haider N,et al..Apoptosis in atherosclerosis.Does it contribute to plaque instability[J].Cardiol Clin,2004,19(1):127-139.
[19]张运,张鹏飞.易损斑块的研究现状[J].中国处方药.2005,39(6):6-9.
[20]Tanaga K,Bujo H,Inoue M,et al.Increased circulating Malondialde hyde-modified LDL levels in patients with coronary artery diseases and their association with peak sizes of LDL particles[J].Arterioscler Thromb Vasc Biol,2002,22:662-666.
[21]Sotirios T,Claes B,Reinaldo W,et al.Temporal increases in plasma markers of oxidized low density lipoprotein strongly reflect the presence of acute coronary syndrome[J].J Am Coll Cardio,2003,3:360-370.
[22]唐雅玲,杨永宗.AS斑块内血管新生的研究进展[J].心血管病学进展,2004,21(增刊):1-5.
[23]Farmer JA,Gotto AM.Dyslipidemia and vulnerable plaque[J].Prog Cardiovasc Dis,2002,44(6):415-428.
[24]Schmermund A,Rodemann J,Erbel R.Intracoronary thermography[J].Herz.2003,28(6):505-512.
[25]王卫明.C反应蛋白的研究进展[J].心血管病学进展,2005,26(1):73.
[26]黄玮,陈庆伟,雷寒,等.纤维蛋白原与高敏C反应蛋白对稳定性冠心病患者心血管事件的预测价值[J].中华心血管病杂志,2006,34(8):718-721.
[27]Pearson TA,Mensah GA,Alexander RW,et al.Markers of inflammation and cardio-vascular disease:application to clinical and public health practice:a statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association[J].Circulation,2003,107:499-511.
[28]CushmanM,Arnold AM,Psaty BM,et al.C-reactive protein and the 10-year incidence of coronary heart disease in oldermen and women:the cardiovascular health study[J].Circulation,2005,112(1):25-31.
[29]董解菊,李真,何作云.高敏C反应蛋白作为冠心病危险因子的临床应用价值[J].国外医学临床生物化学与检验学分册,2005,26:697-699.
[30]Schwartz RS,Bayes-Genis A,Lesser JR,et al.Detecting vulnerable plaque using peripheral blood:inflammatory and cellular markers[J].J interv Cardiol,2003,16(3):231-242.
[31]罗俊,李珂,燕平伯.他汀类药物临床试验及应用最新进展[J].心血管病学进展.,2005,26:33-35.
[32]Schwartz GG,Olsson AG,Ezekowitz MD,et al.For the myocardial ischemia reduction with aggressive cholesterol lowering(MIRACL) study investigators.Effects of atorvastatin on early recurrent ischemic events in acute coronary syndrome:the MIRACL study:a randomed controlled trial[J].JAMA,2001,285:1711-1718.
[33]Cannon CP,Braunwald E,McCabe CH,et al.Comparison of intensive and moderate lipid lowering with statins after acute coronary syndrome[J].N Engl J Med,2004,350(15):1495-1504.
[34]Charles E,Rackle MD.Cardiovascular basis for cholesterol therapy[J].Cardiol in Rev,2000,49(8):124-131.
[35]John A,Ambrose,MD,David J,et al.Classification of systemic therapies for potential stabilization of the vulnerable plaque to prevent acute myocardial infarction[J].Am J Cardiol,2005,95(3):379-382
[36]The HOPE Investigators.The heart Outcomes Prevention Evaluation Study[J].N Engl J Med,2000,342(10):145-153.
[37]The EUROPA trial Investigators.The European trial on reduction of cardiac events with peridolpril in stable coronary artery disease[J].Lancet,2003,62(3):782-788.
[38] Naghavi M, Barlas Z, Siadaty S, et al. Association of influenza vaccination and reduced risk of recurrent myocardial infarction[J]. Circulation, 2000, 102(25): 3039- 3045.
[39] Huittinen T,Leinonen M, Tenkanen L et al.Autoimmunity to human heart shock protein 60, Chlamydia pneumonine infection ,and inflammation in predicting coronary risk[J]. Arterioscler Thromb Vasc Biol, 2006, 22: 431-437.
[40] Nichol KL, Nordin J, Mullooly J, et al. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly[J]. 2003, 348(14): 1322-1332.
[1]王东升,袁肇凯,陈方平.动脉粥样硬化“痰瘀”病理的理论探讨[J].湖南中医学院学报,2004,24(5):27-29.
[2]程康林,覃勇,陈仁山,等.痰浊型冠心病患者痰浊证与颈动脉斑块的相关性分析(J].新中医,2006,38(8):20-21.
[3]周仲瑛,金妙文,顾勤,等.滋肾养肝、化痰消瘀法治疗AS的理论探讨[J].南京中医药大学学报(自然科学版),2002,18(3):137-139.
[4]肖颖,王友民.动脉粥样硬化中医病机探析(J].陕西中医学院学报,2003,26(6):8-9.
[5]徐浩,陈可冀.冠心病易损斑块与中西医结合干预的实践与思考[J].中西医结合心脑血管病杂志,2006,4(11):941-942.
[6]于俊生,陈兆昌.动脉粥样硬化从痰瘀毒论治探讨[J].山东中医杂志,2002,21(8):451-454.
[7]张京春,陈可冀,张文高,等.不稳定斑块的中西医结合认识现状及研究思路[J].中国中西医结合杂志,2005,25(10):869-871.
[8]周明学,徐浩,陈可冀.中医脂毒、瘀毒与易损斑块关系的理论探讨[J].中国中医基础医学杂志,2007,13(10):737-738.
[9]Calara F,Silvestre M,Casanada F,et al.Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice[J].J Pathol.2001,195(2):257-263.
[10]Johnson JL,Jackson.CL.Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse[J].Atherosclerosis.2001,154(2):399-406.
[11]Rosenfeld ME,Polinsky P,Virmani R,et al.Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse[J].Arterioscler Thromb Vasc Biol.2000,20(12):2587-2592.
[12]文川,徐浩,黄启福,等.活血中药对ApoE缺陷小鼠血脂及AS斑块炎症反应的影响[J].中国中西医结合杂志2005,25(4):345-348.
[13]Bennett MR.Breaking the Plaque Evidence for Plaque Rupture in Animal Models of Atherosclerosis[J].Arteriosclerosis,Thrombosis,and Vascular Biology.2002,22(5):713-714.
[14]文川,徐浩,黄启福,等.几种活血中药对ApoE缺陷小鼠AS斑块的影响[J].中国病理生理杂志2005,21(5):864-867.
[15]袁志兵,李晓辉,李淑慧,等.三七总皂苷对AS斑块稳定性的影响[J]中国天然药物,2006,4(1):62-65.
[16]袁志兵,李晓辉,李淑惠,等.三七总皂苷改善兔AS斑块稳定性的机制探讨[J].中草药,2006,37(5):41-743.
[17]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠血脂和AS斑块炎症反应的影响[J].中国中西医结合杂志.2008,28(2):126-130.
[18]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠AS斑块炎症反应的影响[J].中西医结合心脑血管病杂志,2007,5(12):1202-1205.
[19]鞠镐.大蒜素对AS斑块稳定性的机制研究[博士学位论文][D].北京:北京中医药大学,2005:251-255.
[20]徐浩,文川,陈可冀,等.川芎、赤芍及其有效部位配伍对载脂蛋白E基因缺陷小鼠AS斑块稳定性影响的研究[J].中国中西医结合杂志,2007,27(6):513-518.
[21]张京春,陈可冀,郑广娟,等.解毒活血中药配伍对载脂蛋白E基因敲除小鼠主动脉NF-κB与MMP-9表达的调控作用[J].中国中西医结合杂志,2007,13(1):221-225.
[22]张路,吴宗贵,廖德宁,等.通心络对实验性家兔主动脉粥样硬化斑块内血管内皮生长因子表达的影响[J].中国动脉硬化杂志,2004,12(2):177-182.
[23]张保亭,颜乾麟,颜德馨,等.稳斑护脉颗粒对AS斑块稳定性影响的分子机制[J].中国中西医结合杂志,2005,25(2):154-159.
[24]卫培峰.脑心通胶囊对冠心病病人NO、ET、PGI2、TXB2含量影响的临床观察[J].中西医结合心脑血管病杂志,2003,23(1):99-100.
[25]鹿晓婷,孙秀芳,韩永涛,等.脑心通胶囊和辛伐他汀稳定易损斑块的对比研究[J].中西医结合心脑血管病杂志,2007,9(5):825-827.
[26]赵玉霞,刘运芳,刘艳.脑心通胶囊对不稳定斑块兔TLR-2和TLR-4炎性信号转导因子的影响[J].中西医结合心脑血管病杂志,2006,4(2):1071-1073.
[27]赵玉霞,刘运芳,刘艳,等.祛瘀消斑胶囊对易损斑块的稳定作用[J].中医杂志,2006.47(11):856-858.
[28]王大英,李勇,范维琥.麝香保心丸对心肌梗死大鼠梗死面积和血管新生的作用[J].中成药,2004,26(5):912-915.
[29]罗心平,李勇,范维琥,等.麝香保心丸减少高脂血症对动脉壁损害作用的实验研究[J].中国中西医结合杂志,1998,18(6):486-489.
[30]李天奇,李勇,范维琥.麝香保心丸和辛伐他汀对兔股AS斑块稳定性的影响[J].中华老年心脑血管病杂志,2006,8(5):296-299.
[31]路永刚,张铁忠,程文立,等.通脉益智胶囊增加ApoE基因敲除小鼠易损AS斑块稳定性的作用[J].北京中医药大学学报,2007,30(5):329-333.
[32]蔡宝祥,谢梅林.消瘀片对兔腹主动脉粥样斑块稳定性的影响[J].中医药学刊,2006,24(5):855-857.
[33]姜希娟,杜云,苏金玲,等.心脑血脉宁对家兔易损斑块模型血清CRP和斑块内炎细胞浸润的影响[J].天津中医药,2007,24(5):402-404.
[34]曹源,舒晓春,吴贻金,等.复方丹参滴丸对冠心病基质金属蛋白酶—9和肿瘤坏死因子—α的影响(J].心血管康复医学杂志,2005,14(4):319-321.
[35]王强,王毅.通脉胶囊对AS斑块稳定性影响的实验研究(J).中成药,2004,26(9):732-735.
[36]黄晓松,杨期东,龙光喻,等.通心络胶囊对颈AS不稳定斑块影响的临床研究[J].疑难病杂志,2007,6(5):267-269.
[37]左芳,赵玉霞.通心络胶囊对AS斑块影响的临床研究[J].山东中医杂志2005:24(5):269-271.
[38]丁茹,吴宗贵,潘晓明,等.通心络对急性冠状动脉综合征病人血管细胞黏附分子—1水平影响的研究[J].中西医结合心脑血管病杂志,2005,3(5):377-378.
[39]刘运芳,赵玉霞,于会明,等.祛瘀消斑胶囊对动脉粥样斑块组织学构成的影响[J].中医杂志,2003,44(4):280-281.
[40]王伟华,章辉,喻艳林,等.血脂康对不同血脂水平的急性冠状动脉综合征患者的干预作用[J].中国中西医结合杂志2004;24(12):1073-1076.
[41]田静文,方颖,吴立荣,等.血脂康和阿托伐他汀短期治疗对急性冠状动脉综合征初期患者炎症因子的影响比较[J].中华实用中西医杂志,2004;4(17):1745-1747.
[42]尚德师,张焱,陈咸川,等.化湿泄浊汤对不稳定心绞痛患者高敏C反应蛋白影响的临床研究[J].时珍国医国药,2007,18(2):421-422.
[43]尚德师,张焱,陈成川,等.化湿泄浊汤影响不稳定心绞痛患者IL-6、TNF-α的临床研究(J).辽宁中医杂志,2007,34(6):760-761.
[44]洪永敦,吴辉,莫洪辉,等.香丹注射液治疗急性冠状动脉综合征的临床研究及其对炎症指标的影响[J].中药新药与临床药理,2004,15(6):425-428.
[45]Shiomi M,Ito T,Hirochi Y,et al.Fibromuscular cap composition is important for the stability of established atherosclerotic plaques in mature WHHY rabbits treated with statins[J].Athersclerosis 2001,57(1):75-84.
[1]陈可冀,李连达,翁维良,等.血瘀证与活血化瘀研究[J].中西医结合心脑血管病杂志,2005,3(1):1-2.
[2]姜良铎,张文生.从毒论治初探[J].北京中医药大学学报,1998,21(5):2.
[3]王永炎.关于提高脑血管疾病疗效难点的思考[J].中国中西医结合杂志,1997,17(4):195-196.
[4]刘更生.论毒邪[J].山东中医学院学报,1989.13(1):3.
[5]余林中,郑有顺.中医解毒法研究思路[J].中药药理与临床,1998,14(5):39-41.
[6]邓泽明,叶望云.热毒清抗内毒素DIC家兔肝细胞和线粒体过氧化损伤的实验研究[J].中国中西医结合杂志,1991,11(2):110.
[7]李鸣真,陆付耳.阐明中医清热解毒法的实质[J].健康报,2000,2:21.
[8]吴尧忠,张姗,王殿伦,等.热毒血瘀实验家兔血浆TXB26-kelo-PGF1含量变化的初步观察[J].微循环技术杂志,1996,3(2):130.
[9]卞慧敏,杨进,陈德宁,等.不同造模方法致热毒血瘀证家兔血液流变学改变的比较研究[J].微循环技术杂志,1996,3(2):99.
[10]雷燕.络病制胜论探微[J].北京中医药大学学报,1998,(2):18-23.
[11]卢笑晖.论热毒在急性冠脉综合征发病中的作用[J].中国中医急症,2005,14(8): 751.
[12]杨永宗.AS性心血管病基础与临床[M].北京,科学出版社,2004,578.
[13]Naghavi M,Barlas Z,Siadaty S,et al.Association of influenza vaccination and reduced risk of recurrent myocardial infarction[J].Circulation,2000,102(25):3039-3045.
[14]Nichol KL,Nordin J,Mullooly J,et al.Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly[J].N Engl J Med,2003,348(14):1322-1332.
[15]Huittinen T,Leinonen M,Tenkanen L,et al.Autoimmunity to human heart shock protein 60,Chlamydia pneumonine infection,and nflammation in predicting coronary risk[J].Arterioscler Thromb Vasc Biol,2004,2(3):431-437.
[16]Enrique P,Gurfinkel E,Gerardo B,et al.Trials of anti chlamydiatherapy:emerging role of antibiotics in atherosclerosis[J].Am Heart,1999,138 suppl:s537-s538.
[17]Ross R.Atherosclerosis:an inflammatory disease[J].N Engl J Med,1999,340:115-126.
[18]范砚超,张国平,唐明.从毒论治AS初探[J].山东中医杂志.2002,23(5):261-263.
[19]王鹂,魏陵博,刘学法,等.热毒学说在急性冠脉综合征中的地位[J].中国中西医结合杂志,2005,3(12):1080-1081.
[20]于俊生,陈兆昌.动脉粥样硬化从痰瘀毒论治探讨[J].山东中医杂志,2002,21(8):451.
[21]于俊生,王砚琳.痰瘀毒相关论[J].山东中医杂志,2000,19(6):323-325.
[22]钟敬柏.从“痰瘀蕴毒”论治急性心肌梗死[J].中国中医药信息杂志,2001,8(3):3-4.
[23]周明学,徐浩,陈可冀.中医脂毒、瘀毒与易损斑块关系的理论探讨[J].中国中医基础医学杂志,2007,13(10):737-738
[24]王筠,张军平.冠心病之络脉虚滞论[J].中医药学刊,2006,24(4):629.
[25]Schmermund A,Rodemann J,Erbel R.Intracoronary thermography[J].Herz.2003,28:505-512.
[26]张涛,李自成.冠心病易损斑块的研究进展[J].临床心血管病杂志,2004,20(8):509-513.
[27]朱良春.医学微言[M].北京,人民卫生出版社,1996,98.
[28]丁书文,李晓,李运伦.热毒学说在心系疾病中的构建与应用[J].山东中医药大学学报,2004,28(6):413-417.
[29]王少英.清热解毒药物在治疗冠心病中的运用[J].北京中医,2004.23(1):14-15.
[30]李晓,丁书文,姜萍,等.心和颗粒剂保护冠心病患者血管内皮损伤的临床研究[J].中医杂志,2000,41(11):661.
[31]沈自尹.清热解毒药对感染性炎症作用原理的新认识[J].中国中西医结合杂志1997;17(10):628-629.
[32]付晓春,王敏伟.黄连解毒汤的抗血栓作用研究[J].沈阳药科大学学报,2001,18(6):425-427.
[33]杜艳芝,闫晓梅,胡维诚,等.清热解毒液对高脂血症大鼠内皮素影响的研究[J].中国病理生理杂志,1999,15(12):134-137.
[34]朱平,张学霞.清热解毒方对血管内皮细胞增殖的影响[J].山西中医,2003,19(5):41-43.
[35]郭来,丁书文.复方莶草合剂抗AS内皮细胞损伤实验研究[J].中医药学刊,2001,19(2):105-107.
[36]徐浩,陈可冀.冠心病易损斑块与中西医结合干预的实践与思考[J].中西医结合心脑血管病杂志2006,4(11):941-942.
[37]张京春,陈可冀,张文高,等.不稳定斑块的中西医结合认识现状及研究思路[J].中国中西医结合杂志,2005,25(10):869-871.
[38]Naghavi M,Libby P,Falk E,et al.From vulnerable plaque to vulnerable patient:a call for new definitionsand risk assessment strategies:part Ⅰ[J].Circulation,2003, 108(15):1664-1672.
[39]王卫明.C反应蛋白的研究进展[J].心血管病学进展,2005,26(1):73.
[40]余蓉,冼绍祥,叶秀琳,等.活血解毒疗法对急性冠脉综合征血清sCD40L影响[J].中医药学刊,2006,24(7):1375-1376.
[41]王怀亮.虎杖提取液对冠心病患者血小板释放功能的影响[J].深圳中西医结合杂志,1997,7(2):19-20.
[42]王芝梅.大黄醇提物的药理与临床[J].药物研究.2000,9(4):24.
[43]文川,徐浩,黄启福,等.活血中药对ApoE缺陷小鼠血脂及AS斑块炎症反应的影响[J].中国中西医结合杂志,2005,25(4):345-348.
[44]文川,徐浩,黄启福,等.几种活血中药对ApoE缺陷小鼠AS斑块的影响[J].中国病理生理杂志,2005,21(5):864-867.
[45]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠血脂和动脉粥样硬化斑块炎症反应的影响[J].中国中西医结合杂志.2008,28(2):126-130.
[46]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠动脉粥样硬化斑块炎症反应的影响[J].中西医结合心脑血管病杂志,2007,5(12):1202-1205.
[47]张京春,陈可冀,郑广娟,等.解毒活血中药配伍对载脂蛋白E基因敲除小鼠主动脉NF-κB与MMP-9表达的调控作用[J].中国中西医结合杂志,2007,13(1):221-225.