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LDL胆固醇水平和动脉粥样硬化风险之间存在许多联系，但很明显，LDL的替代因子参与了心血管疾病的发病机制，并且在定义动脉粥样硬化性心脏病的存在或加速进展的风险方面存在很大的改进空间。大量证据支持炎症在动脉粥样硬化发病机制中以特定氧化途径的形式起补充作用。通过在已知的风险降低疗法如HMG-CoA还原酶抑制剂（即“他汀类”）的背景下使用氧化应激的特定测量，我们最近已经显示了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疾病之间的强相关性。详细评估将动脉粥样硬化斑块体积/进展的定量测量与不同的 需要氧化途径。另一个可能参与动脉粥样硬化的过程是胆固醇逆向转运。高密度脂蛋白（HDL）颗粒促进胆固醇从细胞流出。它还被认为促进多种抗氧化和抗炎活性。既没有直接证明孤立的HDL升高对斑块进展的临床影响，也没有HDL抗氧化和抗炎的体内评估。 已经报道了受试者的活动。在初步研究中，我们提供了第一个直接的实验证据，在人类孤立的HDL升高影响动脉粥样硬化斑块进展/消退的速度，通过冠状动脉血管内超声（IVUS）监测。在受试者中静脉输注一种形式的载脂蛋白（apo）A-I 引起冠状动脉斑块体积的显著消退。目前的建议旨在扩展我们最初的临床和生化观察，并系统地研究氧化应激，逆转胆固醇转运的分子机制，以及新发现的这些途径之间的相互联系，影响冠状动脉粥样硬化斑块的进展/消退。我们将通过以下具体目标来实现这一目标：（1）通过对患者进行连续冠状动脉IVUS监测，验证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测量的假设;（2）为了验证apoA-I位点特异性氧化调节HDL胆固醇逆向转运功能的假说，与心血管风险增加相关，相反，孤立的HDL升高通过特定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.