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: 6032130
• 负责人: Thomas N. Tulenko
• 金额: $ 3.29万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 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 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6032130
• 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困扰非裔美国人 比一般美国人更频繁、更严重， 尤其是白人。血管疾病，包括高血压 导致这一领域的发病率和死亡率不成比例地升高 少数群体。为什么非裔美国人的血管疾病发病率较高 尚不清楚，但构成了该提案的主要目标。胰岛素 电阻（IR）已被确定为与 非裔美国人的高血压。 IR 与 IR 有很强的相关性 非洲裔美国人的临界高血压已被记录， 表明这可能与疾病的发展存在因果关系 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、非胰岛素有关 依赖性糖尿病和动脉粥样硬化性血脂异常。这四个 条件构成了发展的主要风险因素 动脉粥样硬化，心肌梗塞、中风的潜在疾病 和跛行，所有这些症状在非裔美国人中均较严重。小的 已知 IR 导致高血压的机制基础 或一般血管功能障碍。本研究将重点关注两个原则 IR 中发生变化且已知对整体影响的因素 脉管系统、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， 高血压非裔美国人增加了 Ca++ 的吸收并升高 与对照受试者相比，细胞溶质 Ca++ 水平。我们还发现升高 血小板膜的胆固醇含量，暗示异常 Ca++ 改变后的血小板膜组成和结构 处理。 IR血脂异常可能介导血小板和动脉平滑肌 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/或脂蛋白的生物学特性和 从而导致动脉疾病的发展，包括 非裔美国人的高血压并解释了他们的高血压 心血管风险。因此，我们将测试：1.) 血小板是否来自 红外线、高血压的非洲裔美国人表现出钙处理的改变， 膜组成/结构和聚集活性； 2.)、是否低密度脂蛋白 从IR来看，高血压的非洲裔美国人可以引起血小板的改变 和人类 SMC 功能和/或改变 Ca++ 代谢； 3.) 是否HDL 从IR来看，高血压的非洲裔美国人可以逆转动脉粥样硬化- 诱导 SMC 功能的改变。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及其作用 对培养中的人类 SMC 细胞的影响。将评估 Ca++ 代谢 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，以期阐明 血小板和脂蛋白改变在 IR 中的作用及其关系 非洲裔美国人的心血管风险。

项目成果

The smooth muscle cell membrane during atherogenesis: a potential target for amlodipine in atheroprotection.

动脉粥样硬化形成过程中的平滑肌细胞膜：氨氯地平预防动脉粥样硬化的潜在靶点。

• DOI: 10.1067/mhj.2001.109947
• 发表时间: 2001
• 期刊: American heart journal
• 影响因子: 4.8
• 作者: Tulenko,TN;Sumner,AE;Chen,M;Huang,Y;Laury-Kleintop,L;Ferdinand,FD
• 通讯作者: Ferdinand,FD