SCOR IN ISCHEMIC HEART DISEASE IN BLACKS

黑人缺血性心脏病专门研究中心 波士顿大学医学院将提供多学科的 微血管功能及其相关功能障碍的研究进展 黑人心血管疾病的发病机制。我们推测 黑人中常见的主要心血管疾病 高血压、左心室肥厚和心肌缺血 没有心外膜冠状动脉疾病--由特定的微血管引起 这是一氧化氮不足的直接后果。 我们提案的这一统一主题是基于越来越多的 有证据表明，许多心血管疾病的特征， 鼠疫黑是由生物活性不足的一氧化氮引起的。的 这种一氧化氮不足的基本机制是 这是该计划的主要重点，我们建议使用 方法的组合，包括分子和细胞研究， 动物研究和临床患者研究。我们不做先验 关于黑人一氧化氮不足是否是主要原因的假设 或继发性事件：有证据支持原发性内皮 在一氧化氮产生的异常之前， 血管疾病，有证据表明， 一氧化氮的生物活性也伴随着血管病变的进展， 疾病该计划中提出的项目将提供一种手段， 评估减少生物活性一氧化氮生成的机制 在临床血管发展之前和之后 在人类和相关动物模型中的表型。项目1将测试 假设微血管内皮细胞产生不足 一氧化氮在黑人，并将通过解决这个问题， 合成或失活的潜在异常。项目2构成为 其核心假设是一氧化氮生物活性受损可以解释 改变细胞内钙稳态，伴随着盐- 敏感国家。平滑肌细胞血管功能和离子通道的研究 肌肉细胞和血小板将被用来解决这个问题。在 项目3一氧化氮在调节潜在的有害 血管紧张素II对心脏的影响将被研究，其主要 假设血管紧张素II可以诱导心脏纤维化， 一氧化氮项目4将重点关注肥大性 心肌和冠状血管系统从盐敏感性和/或硝酸盐 氧化缺陷大鼠缺血再灌注，并将试图减少 缺血再灌注损伤的程度通过选择的药理学和 代谢手段。黑人和老年人血管功能的临床研究 白人将在项目5中进行测试，以检验异常 一氧化氮介导的反应存在于黑人中。使用体内 方法，这些研究者将尝试剖析机制 外周和冠状动脉中潜在的一氧化氮作用减弱 血压正常盐敏感个体和高血压患者的循环 患者因此，有了这种广泛的方法， 发达的血管主题，这SCOR在缺血性心脏病， 黑人应该提供关于原因的重要新知识， 黑人血管疾病的后果，并应导致新的 预防和治疗的方法。

The Ischemic Heart Disease in Blacks Specialized Center of Research at Boston University School of Medicine will provide a multidisciplinary approach to the study of microvascular function and dysfunction relevant to the pathogenesis of cardiovascular disease in blacks. We postulate that the principal cardiovascular disorders common among blacks-- hypertension, left ventricular hypertrophy, and myocardial ischemia without epicardial coronary disease--result from a specific microvascular diathesis that is a direct consequence of nitric oxide insufficiency. This unifying theme for our proposal is based on the growing body of evidence that many of the features of the cardiovascular disorders that plague blacks derive from inadequate bioactive nitric oxide. The fundamental mechanism(s) underlying this nitric oxide insufficiency is a major focus of this program, and we propose to address this issue using a combination of approaches, including molecular and cellular studies, animal studies, and clinical patient studies. We make no a priori assumptions about whether inadequate nitric oxide in blacks is a primary or secondary event: evidence exists in support of a primary endothelial abnormality in nitric oxide production that precedes the development of vascular disease, and evidence exists to suggest that abnormalities in nitric oxide bioactivity also accompany the progression of vascular disease. The projects presented in this program will provide a means to assess the mechanisms for decreased elaboration of bioactive nitric oxide both prior to and following the development of a clinical vascular phenotype in man and in relevant animal models. Project 1 will test the hypothesis that microvascular endothelial cells generate insufficient nitric oxide in blacks, and will approach this problem by addressing potential abnormalities of synthesis or inactivation. Project 2 poses as its central hypothesis that impaired nitric oxide bioactivity can explain altered intracellular calcium homeostasis which accompanies the salt- sensitive state. Vascular function and ion channel studies in smooth muscle cells and platelets will be performed to address this question. In Project 3 the role of nitric oxide in modulating the potentially harmful effects of angiotensin II on the heart will be studied, with its principal hypothesis that angiotensin II can induce cardiac fibrosis in the absence of nitric oxide. Project 4 will focus on the responses of hypertrophic myocardium and coronary vasculature from salt-sensitive and/or nitric oxide-deficient rats to ischemia-reperfusion, and will attempt to reduce the extent of ischemia-reperfusion injury by selected pharmacologic and metabolic means. Clinical studies of vascular function in blacks and whites will be conducted in Project 5 to test the hypothesis that abnormal nitric oxide-mediated responses exist in blacks. Using in vivo approaches, these investigators will attempt to dissect the mechanism(s) underlying blunted nitric oxide action in the peripheral and coronary circulations of normotensive salt-sensitive individuals and hypertensive patients. Thus, with this broad spectrum of approaches centered around a well-developed vascular theme, this SCOR in Ischemic Heart Disease in Blacks should provide important new knowledge on the causes and consequences of vascular disease in blacks, and should lead to new approaches for its prevention and treatment.