BIOLOGICAL MEDIATORS OF ATHEROGENESIS IN BLACK AMERICANS

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Coronary heart disease (CHD) is the major cause of morbidity and mortality in the United States and is also the leading cause of death among black Americans. However, there is increasing evidence that blacks show an increased prevalence of CHD compared to whites. The overall goal of this application is to identify differences in the mechanisms underlying the genesis of CHD in blacks versus whites in order to understand the basis for racial differences in rates of CHD. This project will focus on identifying the important cells and molecules involved in the early pre-atherosclerotic lesion that might mediate local inflammatory responses and growth of the vessel wall. Additional studies will focus on the ongoing process of intimal development through an analysis of mature atheromas and the response of the vessel wall to a therapeutic interventional procedure, angioplasty. These projects will integrate studies of lipid metabolism with monocyte/leukocyte adhesion and transmigration into the vessel wall and atherosclerotic plaque development. Specifically we will test the following hypotheses: a) that there are racial differences in the postprandial metabolism of lipids; b) that altered postprandial lipid metabolism has acute effects on monocyte/leukocyte adhesion and transmigration into the vessel wall through actions modifying the local expression of chemotactic factors or adhesion receptors; c) that there are cellular and/or molecular differences in the vessel wall in blacks compared to whites that might explain racial differences in atherogenesis. In addition these studies will re-examine the monoclonal hypothesis regarding atherosclerotic plaque development by characterizing the cellular distribution of specific isoforms of the glucose-6-phosphatase dehydrogenase enzyme in early fatty streaks and mature atheromas of black females using in situ hybridization with isoform specific probes. This will allow us to determine if atherosclerotic plaques originate from single or multiple cellular event(s) by characterizing zones of monoclonality in early fatty streaks as well as in late atheromas.