PLATELET AND LIPOPROTEIN FUNCTION IN AFRICAN-AMERICANS

高血压和血管功能障碍打击非洲裔美国人， 比一般美国人更频繁和严重， 尤其是高加索人血管疾病，包括高血压 在这方面， 少数群体。为什么血管疾病在非洲裔美国人中升高， 不明确，构成本提案的主要目标。胰岛素 抗性（IR）已被确定为与 非裔美国人的高血压IR与 非裔美国人的临界高血压已经被记录， 这表明，它可能与发展的因果关系， 非裔美国人的高血压有证据表明，IR有助于 不仅与高血压的病因有关，而且与肥胖、非胰岛素 依赖性糖尿病和致动脉粥样硬化性血脂异常。这四 条件构成发展的主要风险因素， 动脉粥样硬化，心肌梗死的潜在疾病，中风 和跛行，所有这些症状在非裔美国人中的发病率都较高。小 已知IR导致高血压的机制基础 或血管功能障碍。本研究将侧重于两个原则 这些因素在IR中改变，并且已知有助于整体 血管系统、循环血小板和血清的健康 脂蛋白初步数据表明，来自IR的血小板， 高血压非裔美国人的Ca++吸收增加，并且升高 与对照受试者相比的胞质Ca++水平。我们还发现 血小板膜的胆固醇含量，这意味着 血小板膜组成和结构与Ca++改变 装卸. IR时血脂异常可能介导血小板减少和动脉平滑肌 肌细胞（SMC）膜异常，从而影响细胞功能 异常我们假设IR有助于改变 循环血小板和/或脂蛋白的生物学性质， 从而导致动脉疾病的发展，包括 非洲裔美国人的高血压，并解释他们的高血压， 心血管风险因此，我们将测试：1.）血小板是否来自 IR，高血压非裔美国人显示钙处理改变， 膜组成/结构和聚集活性; 2.），是否LDL IR导致非裔美国人高血压可诱导血小板变化 和人SMC功能和/或改变Ca++代谢;和3.）是否HDL 高血压的非裔美国人可以逆转动脉粥样硬化 导致SMC功能改变。本研究将使用新鲜分离的 血小板和脂蛋白，研究它们之间的相互作用， 对培养的人SMC细胞的影响。将评估Ca++代谢 利用~（45）Ca ~（++）和Fura-2技术， 使用X射线衍射技术进行评估， 血小板和脂蛋白改变在胰岛素抵抗中的作用及其相互关系 对非裔美国人心血管疾病的风险。

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.