PLATELET AND LIPOPROTEIN FUNCTION IN AFRICAN-AMERICANS

非裔美国人的血小板和脂蛋白功能

• 批准号: 2519398
• 负责人: Thomas N. Tulenko
• 金额: $ 18.23万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1998-11-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519398
• 关键词: African American; atherosclerosis; blood lipoprotein; blood vessel disorder; calcium flux; essential hypertension; high density lipoproteins; human tissue; insulin sensitivity /resistance; laboratory rabbit; low angle X ray diffraction analysis; low density lipoprotein; platelet aggregation; vascular smooth muscle

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.

高血压和血管功能障碍对非裔美国人的影响 比一般美国人更频繁，更严重， 尤其是高加索人。血管疾病，包括高血压 导致了不成比例的高发病率和高死亡率 少数群体。为什么血管疾病在非裔美国人中增加 不清楚，并构成这项提案的主要目标。胰岛素 抗性(IR)已被确定为与 非裔美国人的高血压。与IR有很强的相关性 非洲裔美国人的临界高血压已经被记录在案， 这表明它可能与 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，还与肥胖、非胰岛素有关 依赖型糖尿病和致动脉粥样硬化性血脂异常。这四个人 条件是……发展的主要风险因素 动脉粥样硬化，心肌梗死、中风的潜在疾病 和笨拙，所有这些在非裔美国人中都有所增加。一点儿 已知IR导致高血压的机制基础 或一般的血管功能障碍。这项研究将侧重于两个原则 在IR中发生变化并已知对总体有影响的因素 血管系统、循环血小板和血清的健康状况 脂蛋白。初步数据显示来自IR的血小板， 高血压非裔美国人钙摄取增加并升高 细胞内钙离子水平与对照组比较。我们还发现 血小板膜胆固醇含量，提示糖尿病患者存在异常 血小板膜成分和结构与钙离子的变化 正在处理。胰岛素抵抗的血脂异常可能介导了血小板和动脉的通畅 肌肉细胞(SMC)膜异常，从而影响细胞功能 异常现象。我们假设IR有助于改变 循环中血小板和/或脂蛋白的生物学特性及 从而促进动脉疾病的发展，包括 非裔美国人中的高血压及其升高的原因 心血管风险。据此，我们将测试：1.)无论血小板是否来自 IR，高血压的非裔美国人表现出钙处理的改变， 膜的组成/结构和聚集活性；2.)，低密度脂蛋白 从IR来看，非裔美国人高血压可以引起血小板的改变 和人的SMC功能和/或改变钙离子代谢；高密度脂蛋白是否 从IR，高血压的非裔美国人可以逆转动脉粥样硬化- 引起SMC功能改变。这项研究将使用新鲜分离的 研究血小板和脂蛋白之间的相互作用及其相互作用 对体外培养的人SMC细胞的影响。将对CA++代谢进行评估 使用45Ca++和Fura-2技术，以及膜结构参数 使用x射线衍射技术进行评估，以努力阐明 血小板和脂蛋白改变在胰岛素抵抗中的作用及其关系 对非裔美国人的心血管风险。