PLATELET AND LIPOPROTEIN FUNCTION IN AFRICAN-AMERICANS

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High blood pressure and vascular dysfunction strike African Americans with greater frequency and severity than the American population in general, and Caucasians in particular. Vascular disease, including hypertension accounts for a disproportionately elevated morbidity and mortality in this minority group. Why vascular disease is elevated in African Americans is not clear and constitutes a primary objective of this proposal. Insulin resistance (IR) has been identified as a factor cosegregating with hypertension in African Americans. A strong correlation of IR with borderline hypertension in African Americans has been documented, suggesting that it may be causally related to the development of hypertension in African Americans. There is evidence that IR contributes not only to the etiology of hypertension, but also to obesity, non-insulin dependent diabetes mellitus and atherogenic dyslipidemia. These four conditions constitute the cardinal risk factors for the development of atherosclerosis, the underlying disorder in myocardial infarction, stroke and claudication, all of which are elevated in African Americans. Little is known of the mechanistic basis by which IR contributes to hypertension or vascular dysfunction in general. This study will focus on two principle factors which are altered in IR and known to contribute to the overall well being of the vasculature, circulating platelets and serum lipoproteins. Preliminary data indicates that platelets from IR, hypertensive African Americans have augmented Ca++ uptake and elevated cytosolic Ca++ levels compared to control subjects. We also found elevated cholesterol content of the platelet membrane, implicating abnormalities in platelet membrane composition and structure with the altered Ca++ handling. The dyslipidemia of IR may mediate platelet and arterial smooth muscle cell (SMC) membrane abnormalities and thus, cell function abnormalities. We hypothesize that IR contributes to alterations in the biological properties of circulating platelets and/or lipoproteins and thereby contributes to the development of arterial disease, including hypertension in African Americans and explains their elevated cardiovascular risk. Accordingly, we will test: 1.) whether platelets from IR, hypertensive African Americans display altered calcium handling, membrane composition/structure and aggregatory activity; 2.), whether LDL from IR, hypertensive African Americans can induce alterations in platelet and human SMC function and/or alter Ca++ metabolism; and 3.) whether HDL from IR, hypertensive African Americans can reverse atherosclerosis- induced alterations in SMC function. This study will use freshly isolated platelets and lipoproteins to study their mutual interactions and their effects on human SMC cells in culture. Ca++ metabolism will be assessed using 45Ca++ and Fura-2 techniques, and membrane structural parameters assessed using x-ray diffraction techniques in an effort to shed light on the role of altered platelets and lipoproteins in IR and its relationship to cardiovascular risk in African Americans.