SCOR IN ISCHEMIC HEART DISEASE IN BLACKS

波士顿大学医学院黑人缺血性心脏病专门研究中心将提供一种多学科方法来研究与黑人心血管疾病发病机制相关的血管功能和功能障碍。我们推测，黑人中常见的主要心血管疾病高血压、左心室肥大和心肌缺血（无心外膜冠状动脉疾病）是由氧化应激增加导致的特定血管素质引起的。我们的提案的这个统一主题代表了SCOR支持的前五年的直接结果，在此期间，我们证明了黑人血管素质的一个组成部分是一氧化氮不足，我们发现这是其增加的氧化失活的结果。这种增加的氧化应激的基本机制是该计划的主要重点，我们建议使用多种方法来解决这个问题，包括分子，细胞和遗传研究;动物实验;和人类研究。该计划中提出的项目将侧重于保护免受氧化应激所必需的关键细胞机制，特别是将重点关注非洲裔美国人中常见的葡萄糖-6-磷酸脱氢酶（G6 PD）。项目1将检验以下假设：G6 PD作为还原型烟酰胺腺嘌呤二核苷酸磷酸（NADH）和间接谷胱甘肽的最重要细胞来源，其缺乏将通过降低抗氧化保护和增强一氧化氮的氧化失活导致血管功能障碍。项目2提出了核心假设，即G6 PD是动脉粥样硬化环境中NAD（P）H氧化酶产生超氧化物的关键决定因素。在项目3中，将评估G6 PD缺乏在心肌缺血-再灌注损伤中的作用，并评估在G6 PD缺乏状态下增强抗氧化能力的潜在益处。项目4是该项目的一个新项目，将重点关注心肌细胞中G6 PD的消耗将导致活性氧产生增加，导致肥大，胎儿基因表达和凋亡，作为不良梗死后重塑的一种细胞机制。将在项目5中进行人类受试者研究，以检验G6 PD缺乏症与血管系统中氧化应激增加以及伴随的动脉内皮源性一氧化氮生物活性丧失相关的假设;重要的是，将通过对每个研究个体的比活性测量和基因测序来定义G6 PD缺乏症。因此，通过围绕完善和整合的心血管主题的广泛方法，黑人缺血性心脏病的SCOR应继续提供机会，以确定黑人血管疾病原因和后果的重要新机制，并应导致其预防和治疗的新方法。

The Ischemic Heart Disease in Blacks Specialized Center of Research at Boston University School of Medicine will provide a multi-disciplinary approach to the study of vascular 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 vascular diathesis that is a consequence of increased oxidant stress. This unifying theme for our proposal represents a direct outgrowth of the first five years of SCOR support during which we demonstrated that one component of the vascular diathesis of blacks is nitric oxide insufficiency, which we find to be a consequence of its increased oxidative inactivation. The fundamental mechanism(s) underlying this increased oxidant stress is a major focus of this program, and we proposed to address the issue using a combination of approaches, including molecular, cellular, and genetic studies; animal experiments; and human studies. The projects presented in this program will focus on critical cellular mechanisms essential for protection form oxidant stress, and, in particular, will focus on one whose deficiency is common among African Americans, glucose-6-phosphate dehydrogenase (G6PD). Project 1 will test the hypothesis that a deficiency of G6PD, as the most important cellular source of reduced nicotinamide adenine dinucleotide phosphate (NADH) and, indirectly, glutathione, will lead to vascular dysfunction by decreased antioxidant protection and enhanced oxidative inactivation of nitric oxide. Project 2 poses the central hypotheses that G6PD is a critical determinant of superoxide production by NAD(P)H oxidases in the atherosclerotic milieu. In Project 3, the role of G6PD deficiency in myocardial ischemia-reperfusion injury will be assessed and the potential benefits of enhancing antioxidant capacity in G6PD-deficient states evaluated. Project 4, a new project for the program, will focus on the hypothesis that depletion of G6PD in cardiac myocytes will lead to increased reactive oxygen species generation resulting in hypertrophy, fetal gene expression, and apoptosis, serving as one cellular mechanism for adverse post-infarction remodeling. Human subject studies will be performed in Project 5 to test the hypothesis that G6PD deficiency is associated with an increase in oxidant stress in the vasculature and in accompanying loss of arterial endothelial-derived nitric oxide bioactivity; importantly, G6PD deficiency will e defined by specific activity measurements and gene sequencing for each individual studied. Thus, with this broad spectrum of approaches centered around a well- developed and well-integrated cardiovascular theme, this SCOR in Ischemic Heart Disease in Blacks should continue to provide the opportunity to identify important new mechanisms on the causes and consequences of vascular disease in blacks, and should lead to new approaches for its prevention and treatment.