Determinants of Coronary Atherosclerotic Plaque Progression/Regression

高胆固醇血症在动脉粥样硬化形成中起着关键的促进作用。然而，尽管低密度脂蛋白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，替代低密度脂蛋白的因素参与了心血管疾病的发病机制，在确定存在或加速进展的动脉粥样硬化性心脏病的风险方面仍有很大的改进空间。大量证据支持炎症在动脉粥样硬化的发病机制中以特定氧化途径的形式发挥补充作用。通过在HMG-CoA还原酶抑制剂(即他汀类药物)等已知降低风险的治疗方法中使用特定的氧化应激措施，我们最近显示出不同的氧化途径，如涉及一氧化氮和髓过氧化物酶衍生的氧化剂的氧化途径与人类动脉粥样硬化性疾病之间存在强烈的相关性。详细的评估将动脉粥样硬化斑块体积/进展的定量测量与不同的 氧化途径是必需的。另一个可能参与动脉粥样硬化的过程是胆固醇的反向运输。高密度脂蛋白(高密度脂蛋白)颗粒促进胆固醇从细胞外流。它还被认为具有多种抗氧化和抗炎活性。既没有直接证明孤立的高密度脂蛋白升高对斑块进展的临床效果，也没有在体内评估高密度脂蛋白的抗氧化和抗炎作用 已经报道了受试者的活动。在初步研究中，我们首次在人类中提供了直接的实验证据，即通过冠状动脉血管内超声(IVUS)监测，孤立的高密度脂蛋白升高会影响动脉粥样硬化斑块的进展/消退率。受试者静脉输注一种形式的载脂蛋白A-I 引起冠状动脉斑块体积显著减少。目前的建议旨在扩大我们最初的临床和生化观察，并系统地研究氧化应激、胆固醇反向运输以及这些途径之间新发现的相互联系对冠状动脉粥样硬化斑块进展/消退的影响的分子机制。我们将实现这一目标，具体目标如下：(1)检验特定氧化途径的遗传和生化决定因素独立预测冠状动脉粥样硬化斑块体积和进展的定量指标的假设，如患者的连续冠状动脉IVUS所监测；以及(2)检验apoA-I的位点特异性氧化调节高密度脂蛋白的反向胆固醇运输功能与增加心血管风险相关的假说，相反，孤立的高密度脂蛋白升高通过特定的途径促进全身抗氧化作用。

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.