Determinants of Coronary Atherosclerotic Plaque Progression/Regression

冠状动脉粥样硬化斑块进展/消退的决定因素

• 批准号: 6892787
• 负责人: Stanley L Hazen
• 金额: $ 50.49万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892787
• 关键词: apolipoproteins; atherosclerosis; atherosclerotic plaque; cardiovascular disorder risk; cardiovascular imaging /visualization; cholesterol; coronary disorder; genetic susceptibility; high density lipoproteins; human subject; lipid transport; mass spectrometry; medical complication; myocardial infarction; oxidation; oxidative stress; patient oriented research; single nucleotide polymorphism; ultrasound

Hypercholesterolemia plays a critical enabling role in atherogenesis. However, despite the many links between LDL cholesterol levels and atherosclerotic risk, it is clear that factors alternative to LDL participate in the pathogenesis of cardiovascular disease, and substantial room exists for improvement in defining risk for the presence of, or accelerated progression of, atherosclerotic heart disease. Substantial evidence supports a complementary role for inflammation, in the form of specific oxidative pathways, in the pathogenesis of atherosclerosis. Through use of specific measures of oxidant stress in the setting of known risk-reducing therapies such as HMG-CoA reductase inhibitors (i.e. "statins"), we have recently shown strong correlations between distinct oxidative pathways, such as those involving nitric oxide and myeloperoxidase derived oxidants, and atherosclerotic disease in humans. Detailed assessments linking quantitative measures of atherosclerotic plaque volume/progression to rigorous measurements of distinct oxidative pathways are needed. Another process that likely participates in atherosclerosis is reverse cholesterol transport. The high-density lipoprotein (HDL) particle facilitates cholesterol efflux from cells. It also is believed to promote multiple anti-oxidant and anti-inflammatory activities. Neither direct demonstration of a clinical effect of isolated HDL elevation on plaque progression, nor in vivo assessments of HDL anti-oxidant and anti-inflammatory activities in subjects have been reported. In preliminary studies we provide the first direct experimental evidence in humans that isolated HDL elevations impact upon rates of atherosclerotic plaque progression / regression, as monitored by coronary intravascular ultrasound (IVUS). Intravenous infusions of a form of apolipoprotein (apo) A-I in subjects elicited significant regression of coronary artery plaque volume. The present proposal aims to extend upon our initial clinical and biochemical observations and systematically investigate molecular mechanisms of oxidant stress, reverse cholesterol transport, and newly identified interconnections between these pathways, that impact upon coronary artery atherosclerotic plaque progression/regression. We will achieve this with the following specific aims: (1) To test the hypothesis that genetic and biochemical determinants of specific oxidative pathways independently predict quantitative measures of coronary atherosclerotic plaque volume and progression, as monitored by serial coronary IVUS in patients; and (2) To test the hypotheses that site-specific oxidation of apoA-I modulates reverse cholesterol transport functions of HDL, is associated with increased cardiovascular risks, and conversely, that isolated HDL elevations promote systemic antioxidant effects through specific pathways.

高胆固醇血症在动脉粥样硬化中起着至关重要的作用。然而，尽管LDL胆固醇水平与动脉粥样硬化风险之间存在许多联系，但很明显，替代LDL的因素参与心血管疾病的发病机理，并且存在大量的房间，以改善定义存在或加速性进展的风险，即动脉粥样硬化心脏病的存在。大量证据支持在动脉粥样硬化的发病机理中以特定氧化途径的形式进行炎症的互补作用。通过在已知的降低风险降低疗法（例如HMG-COA还还原酶抑制剂（即“汀类药物”））的情况下使用特定的氧化应激措施，我们最近在明显的氧化途径（例如涉及涉及一氮氧化物和骨髓氧化酶衍生的氧化酶，氧化剂氧化剂，氧化剂）和Atherscleritoic病中的明显氧化途径之间表现出牢固的相关性。详细评估，将动脉粥样硬化斑块量/进展的定量测量与严格测量 需要氧化途径。可能参与动脉粥样硬化的另一个过程是反向胆固醇运输。高密度脂蛋白（HDL）颗粒促进了细胞的胆固醇外排。还认为它可以促进多种抗氧化剂和抗炎活性。既不直接证明孤立的HDL升高对牙菌斑进展的临床作用，也没有直接证明HDL抗氧化剂和抗炎的体内评估 已经报道了受试者的活动。在初步研究中，我们提供了人类中的第一个直接实验证据，即分离的HDL升高会影响动脉粥样硬化斑块的进展 /回归率，如冠状动脉内部超声（IVUS）所监测的那样。对受试者中载脂蛋白（APO）A-a形式的静脉输注 引起了冠状动脉斑块体积的显着回归。本提案旨在扩展我们的初始临床和生化观察结果，并系统地研究氧化应激，反向胆固醇转运的分子机制，以及这些途径之间新鉴定的互连，这会影响冠状动脉动脉粥样硬化的进展/回归。我们将以以下特定目的来实现这一目标：（1）检验以下假设：特定氧化途径的遗传和生化决定因素独立预测患者的连续冠状动脉IVUS监测的冠状动脉粥样硬化斑块体积和进展的定量测量； （2）测试ApoA-I的位点特异性氧化的假设调节HDL的反向胆固醇转运功能与心血管风险的增加有关，相反，分离的HDL升高可通过特定途径促进全身抗氧化剂效应。