摘要
第一部分2型糖尿病患者血清HIF-1α与冠脉钙化之间的关系研究背景
动脉粥样硬化是迄今为止导致冠心病、脑卒中、外周动脉血管疾病最常见的病因,有着较高的发病率和死亡率。动脉粥样硬化斑块损害的进展与巨噬细胞脂质超载、局部炎症和血管增加有关,而动脉钙化是动脉粥样硬化突出的特征,能被放射成像技术如EBCT快速、无创性的定量。既往研究研究结果证明大量的冠脉钙化能预测心梗和猝死风险的增加。在糖尿病患者,动脉钙化既可作为粥样斑的成分(内膜钙化),也可以在没有粥样硬化斑块的情况下产生(中膜钙化或蒙氏硬化)。中膜钙化和糖尿病的严重程度和/或持续时间有关,一般影响不易发生动脉粥样硬化的动脉。虽然有一些报道提示中膜钙化和心血管并发症风险的增加有关,但这并不是一致的发现。特别是,冠状动脉中膜钙化很少见,意味着一旦在冠脉中发现钙化,几乎可以肯定和内膜斑块有关。目前已被证明,内膜粥样斑块病变的钙化不仅是慢性血管炎症的被动后果,而是一个主动的过程,能导致钙化和炎症的正反馈,促使动脉粥样硬化疾病进一步进展。现代研究显示血管和骨骼钙化具有相似性,提示在心血管疾病的发展中成骨和钙化因素具有调控作用。
冠心病的发生发展是一个动态变化、缓慢进行的病理生理过程。有研究表明,约50%-60%的心肌梗死发生于冠状动脉没有明确梗阻性狭窄无典型症状的患者22。对于这些无心血管症状患者,如何早期发现冠状动脉粥样硬化病变情况,包括斑块负荷及狭窄变化,早期进行干预和控制就显得具有重要的临床意义。冠状动脉钙化(coronary artery calcification, CAC)几乎存在于所有的动脉粥样硬化病变中,是动脉粥样硬化的特征23-24。在动脉粥样硬化早期的管壁中就可以发现钙化斑块的沉积。冠脉钙化积分可以反映粥样斑块的负荷情况,有助于早期发现不稳定斑块,从而对患者进行早期干预,进而防止恶性心血管事件的发生。
在人类动脉粥样硬化的巨噬细胞聚集区域检测到了低氧环境的存在,证实了低氧存在于动脉粥样硬化斑块中。低氧可能通过促进脂质聚集、增加炎症和血管新生而促进斑块损害进展。在动脉粥样硬化早期,致动脉粥样硬化的脂质蛋白被巨噬细胞从动脉内膜清除,通过积累而形成泡沫细胞。低氧增加巨噬细胞脂滴形成,促进炎症介质的增加。脂滴在介导炎症反应时具有一定的作用。有些文献认为,斑块深层的低氧可通过激活某些血管生成蛋白诱导血管新生。
低氧诱导因子作为低氧的关键调节物,通过激活和促进泡沫细胞形成、诱导内皮细胞功能障碍、细胞凋亡和增加炎症、血管形成等机制,在动脉粥样硬化的进展中具有着重要的作用。氧平衡的破坏可促成动脉粥样硬化的形成。当动脉粥样硬化进展时,由于动脉壁厚度的增加,氧气弥散进入动脉内膜是显著的减少。当细胞供氧减少时,转录因子低氧诱导因子1(Hypoxia-inducible factor1,HIF-1)在细胞适应低氧环境时起着核心的作用。另外,HIF-1可促成动脉粥样硬化各组成成分的功能障碍,增加局部炎症和血管形成。HIF-1对冠脉钙化有无影响,目前还没有临床研究来证实。
目标：
低氧诱导因子(HIF-1)是维持氧平衡的关键因素,由HIF-1α和HIF-1β两个亚基组成,目前发现组织中的HIF-1与软骨和血管钙化相关。本研究的目标是明确在2型糖尿病患者中,外周循环中的HIF-1α水平和冠脉钙化(CAC)之间有无相关性。
方法：
根据ADA和WHO指南,405名既往无心血管疾病证据的2型糖尿病患者被连续纳入研究,具有任何排除标准者将不被纳入。选择标准是2型糖尿病发病持续时间大于一年且发病年龄>35岁。患者具有下列情形将不被纳入研究,包括：心衰或心肌病史,冠心病,静息心电图异常(如Q波,LBBB),脑血管或外周动脉疾病,肾功能不全,乙型、丙型肝炎或已知的其他肝脏疾病,肝脏转氨酶超过正常上限3倍,溶血性疾病,大量饮酒史者,肿瘤、甲状腺疾病,急性传染/炎症情形,使用肝脏毒性药物。同时完成体格检查,记录包括身高、体重指数(body mass index, BMI)、血压和12导联心电图。
根据指南的要求记录患者危险因素情况,危险因素包括：年龄(男性>45岁,女性>55岁)；现在吸烟,定义为在过去的1个月中吸烟；一级亲属早发心血管病家族史(父母、兄弟姐妹或子女,男性<55岁,女性<65岁)；高血压,定义为收缩压/舒张压140/90mmHg或正在服用降压药物治疗；血脂异常,定义为血清总胆固醇>2OOmg/dl或甘油三脂>1.7mmol/L或HDL-C<1.04mmol/L(男)或<1.30mmol/L(女),或正在服用降脂药物治疗。所有患者UKPDS(United Kingdom Prospective Diabetes Study)风险积分于基线时被记录。
研究人群包括262名男性和143名女性,平均年龄51.3±6.4岁。使用ELISA方法测量血清HIF-1α、IL-6(interleukin-6)水平。CAC积分由320CT进行扫描测定。根据血清HIF-1a水平将患者进行四分位数法分组。
结果：
血清HIF-lα平均水平为184.4±66.7pg/ml。在具有较高CAC积分的患者中,HIF-1a水平也显著的增加(P<0.001)。HIF-1α水平与CRP、IL-6、UKPDS风险积分、HbAlc、FBG和CAC积分呈显著的正相关性,但与糖尿病持续时间、年龄、LDL不相关。多元逻辑回归分析显示,HIF-1α水平能独立的预测冠脉钙化的存在。ROC曲线分析显示,HIF-1α水平能预测冠脉钙化的严重程度,但特异性低于传统的危险因素UKPDS风险积分和HbA1c。
结论：
作为低氧的标志物,血清HIF-1α水平可能是冠脉钙化存在的独立危险因素。本研究显示升高的血清HIF-1α水平可能涉及2型糖尿病患者的血管钙化。
第二部分心衰患者循环中HIF-1α的表达及其与心功能之间的关系研究研究背景
低氧诱导因子是在低氧的肝癌细胞株细胞核提取物中发现的能特异性地结合于红细胞生成素基因增强子的寡核苷酸序列,其在氧感受和低氧信号转导机制中普遍起作用。HIF-l α作为一种核转录因子,是维持体内氧稳态平衡调节的主要因子,在哺乳动物的正常生长发育过程和生理以及病理反应过程中都具有重要的作用。在人体内,目前发现HIF-1α可调控人体的100多个基因。Manalo等报道,动脉上皮细胞内的HIF-1α基因可调节超过2%的人类基因。这些基因产物在细胞增殖、葡萄糖和能量代谢、血管形成和重塑等方面具有重要作用。对HIF-1α活性的调节,未来可能成为治疗多种疾病的靶点。近年来,通过对HIF-1α调控机制的研究,我们对HIF-1α的认识达到了一个全新的水平。HIF-1α除了参与它所介导的基因适应低氧外,还有参与常氧条件下其它细胞生理和病生理过程。如正常组织或肿瘤生长、细胞生存、死亡,以及适应应激反应2等,在这种情况下HIF-1a的调节不依赖氧分压,而是依赖各种刺激物,比如生长因子和细胞因子等。HIF-1α活性的向上调节可以增加缺氧组织的血管生成；另一方面,HIF-la下调则能够阻止血管生成,从而使缺氧或炎症组织的存活能力降低。各种与HIF-lα过表达相关的疾病,如肿瘤血管重塑和其他与血管发生相关的疾病。可应用HIF-la抑制剂进行临床治疗。所以目前将HIF-lα作为治疗各类肿瘤的靶点的研究已越来越多,如结肠癌、肺癌、乳腺瘤、卵巢癌等。利用上调HIF-la活性治疗局部缺血缺氧疾病的研究也在进行中,如急性心梗、糖尿病、脑梗死等疾病的前期试验。
在各种心脏疾病中,心肌都有不同程度的缺血缺氧。近年来基础和临床实验表明,心肌缺血可以引起HIF-1α表达明显增加,使机体对心肌缺血缺氧产生代偿性适应,如缩小急性心肌梗死患者梗死范围,促进侧支循环形成,提高心肌缺血预适应能力,启动B型尿钠肽的心脏保护性作用、参与细胞凋亡过程、减轻心肌缺血/再灌注损伤等。HIF-1α作为转录调节因子,介导了缺氧时的重要生理反应,在心血管疾病的发生发展中发挥重要作用,越来越多的研究利用转录因子HIF-1α来调控多种血管生成因子的表达,从而对缺血心肌进行基因治疗。目前针对HIF-1α的研究多局限于动物实验和急性心肌梗塞患者中。随着我国目前正逐步步入老龄化社会,充血性心力衰竭患者在门急诊就诊患者中越来越多见。如何提高这些患者的生活质量、改善他们的预后也成为了研究的热点和重点。之前有文献报道,在大鼠心衰模型中,HIF-1α能启动大鼠心肌细胞产生BNP,对心肌产生保护作用。对于心衰患者,HIF-1α是否在其体内表达,其基因表达量的多少与心功能分级是否具有平行关系,其能否预测心衰患者的预后,目前还没有研究证实。
心衰多是各种心血管疾病终末期表现,在工业化国家和老年化社会尤其多见。心衰患者由于肺循环和体循环的淤血以及心脏泵功能衰竭致使组织灌注不足,最终导致多个器官的缺血、缺氧。正常心脏产生ATP是通过脂肪酸氧化。心衰时心肌细胞处于缺氧状态,转为利用葡萄糖作为糖酵解代谢的底物,脂肪酸被转化为脂质。这种代谢重新编程的结果是失败的,不能产生足够的ATP维持心脏功能。心脏功能的缺失以射血分数下降、LVED增加为特征并出现心衰的临床症状和体征。目前认为,从氧化代谢向糖酵解代谢转化的关键是由HIF-1介导的细胞内适应低氧。另外,通过激活PPAR-γ转录,HIF-1也介导脂肪酸向脂质合成的转化。HIF-1通过调节血管发生和血管重塑控制着氧的传递。另外。HIF-1通过调节葡萄糖代谢和氧化还原平衡控制着氧的利用。近年来的研究表明,心肌缺氧可以引起HIF-1α表达明显增加。HIF-1α作为转录调节因子,通过对下游靶基因的调节,介导了缺氧时的重要生理反应,使机体对心肌缺氧产生代偿性适应。对动物模型分析显示,HIF-1在缺血性心脏病和压力负荷型心衰的病理生理学方面具有关键性的保护作用。
BNP是一种内源性物质,属于尿钠肽家族。它主要在心室肌细胞合成,在维持身体体液平衡和调节血压方面具有重要的作用。在心衰患者中,循环中的BNP水平和疾病的严重程度具有直接的联系。目前越来越多的使用BNP来作为心衰诊断和预后的标志物。有研究者利用人类心室肌细胞的体外模型系统,在没有血流动力学和神经激素的刺激下,证实低氧通过HIF-1α依赖机制直接增加心室肌细胞合成和分泌BNP。然而,在心衰病人中,循环中HIF-1α表达的状况以及与BNP这种心衰的标志物是否直接相关,目前仍不明确。
目标：
HIF-1作为转录因子介导了低氧时重要的生理反应。心衰患者由于心肌缺氧可诱导HIF-1的大量表达。在没有血流动力学和神经激素的刺激下,低氧通过HIF-1α依赖机制直接增加心室肌细胞合成和分泌BNP。因此,本研究首次利用心衰患者作为研究对象,明确HIF-1α在心衰患者的表达及其与BNP之间的关系。
方法：
本研究共连续纳入心衰患者76名,其中急性左心衰患者47名(61.8%),平均年龄73.4±13.4岁。我们使用了ELISA法对患者循环中的HIF-1α水平和BNP水平进行了检测。我们按患者心功能水平进行分组,并进行统计分析。结果：
心衰患者平均血清HIF-1a水平为2.83±0.52ng/ml。心功能Ⅲ级组血清HIF-1α水平为2.67±0.48ng/ml,心功能Ⅳ级组血清HIF-1a水平为2.95±0.52ng/ml,两组之间差异具有统计学意义(P=0.018)。在急性左心衰患者中,血清HIF-1α水平也明显高于慢性心衰患者(3.02±0.44VS2.51±0.49ng/mg,P<0.01)。血清HIF-1α水平SP02,心功能分级和急性左心衰相关,与年龄、SBP、DBP、Nt-Pro BNP和TNI等不相关。血清HIF-1α水平不能独立的预测心衰患者的心功能。
结论：
首次在心衰患者的外周血液循环中发现了HIF-1α这种原本只存在于胞内的蛋白的存在。在我们的研究人群中,虽然血清HIF-1α水平和患者的心功能相关,但其不能独立的预测心衰患者的心功能。
Part I The Relationship Between serum hypoxia-inducible factor la and Coronary Artery Calcification in Uncomplicated type2Diabetic patients
Background:
Hypoxia-inducible factor1(HIF-1), as master regulators of oxygen homeostasis, a heterodimers consists of the subunits HIF-1α and HIF-1β, was implicated in calcification of cartilage and vasculature. The goal of this study was to determine the relationship of serum HIF-1α with coronary artery calcification (CAC) in patients with type2diabetes.
Methods:
The subjects were405asymptomatic patients with type2diabetes mellitus, included262males and143females with a mean (±SD) age of51.3±6.4years old. Serum levels of HIF-1α and interleukin-6(IL-6) were measured by ELISA. CAC scores were assessed by a320-slice CT scanner. The subjects were divided into4quartiles depending on serum HIF-1α levels.
Results:
The average serum HIF-1α level was184.4±66.7pg/ml.AmongpatientswithhigherCAC scores, HIF-1α levels were also significantlyincreased (P<0.001). HIF-1α levels positively correlated withCRP, IL-6, UKPDS riskscore, HbAlc, FBG and CACS, but were not correlated with diabetesduration, age and LDL. According tomultivariate logic analyses, HIF-la levels still significantly independent predict the presence of CAC. Receiver-operating characteristic curve analysis showed that serum HIF-la level can predict the extent of CAC, but the specificity was lower than the traditional risk factors UKPDS and HbAlc.
Conclusions:
As a marker of hypoxia, serum HIF-la level may be an independent risk factor for presence of CAC. These findings indicate that elevated serum HIF-la may be involved in vascular calcification in patients with type2diabetes mellitus.
Part II Relationship betweenHIF-laexpression andcardiac functionamongpatients with heart failure
Objective:
Hypoxia-inducible factor1(HIF-1)mediates many important physiologicalreactions athypoxia situation as a transcriptionfactor. Because of myocardialhypoxia,patients with heart failure caninduceover expressionofHIF-1in vivo. In the absence of hemodynamic or neurohormonal stimuli, hypoxia directly enhances the synthesis and secretion of B-type natriuretic peptide (BNP) in ventricular myocytes, through a HIF-la dependent mechanism. Thus, we designed the first clinical study in order to evaluate the expression of HIFla in patients with heart failure and to determine its relationship with the BNP.
Methods:
76subjects with congestive heart failure were consecutively enlisted, included47acute left heart failure patients. The participants mean age were73.4±13.4years old. Serum levels of HIF-1α and BNP were measured by ELISA. Patients were divided into two groups according to their cardiac function and then to carry out statistical analysis.
Results:
The average serum HIF-la level was2.83±0.52ng/ml. The NYHA Ⅲ patient's serum HIF-1αlevels were2.67±0.48ng/ml. The NYHA Ⅳ patient's serum HIF-lalevels were2.95±0.52ng/ml. A statistically significant differencebetween two groups(P=0.018). Inpatients withacuteleftheart failure, the serum HIF-lalevels were also significantlyhigher thanin patientswith chronic heart failure (3.02±0.44VS2.51±0.49ng/ml, P<0.01). Serum HIF-la levels positively correlated with SPO2, cardiac function and acuteleftheart failure, but were not correlated with age, SBP, DBP, BNP and TNI. According tomultivariate logic analyses, HIF-1α levels cannot independently predicts the cardiac function of heart failure patients.
Conclusions:
Atthe peripheral bloodcirculation ofpatients with heart failure, wefirstdiscovered the existence ofHIF-lawhichoriginally only exists in the intracellular. In ourstudy population,although theserumlevels ofHIF-la was related with cardiacfunction in patients with heart failure, but was notan independent predictorof cardiac function.
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