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.
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