SCOR IN ISCHEMIC HEART DISEASE IN BLACKS

波士顿大学医学院的黑人缺血性心脏病专业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，黑人常见的主要心血管疾病-高血压、左心室肥厚和无心外膜冠状动脉疾病的心肌缺血-是由于氧化应激增加导致的特定血管素质的结果。我们提案的这个统一主题代表了支持SCOR的头五年的直接结果，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，我们发现这是其氧化失活增加的结果。氧化应激增加的基本机制(S)是这个项目的主要焦点，我们建议结合分子、细胞和遗传学研究、动物实验和人体研究来解决这个问题。该计划中提出的项目将集中在保护免受氧化应激的关键细胞机制上，特别是将重点放在非裔美国人中常见的一种缺陷，即葡萄糖-6-磷酸脱氢酶(G6PD)。项目1将测试这样一种假设，即G6PD作为还原的烟酰胺腺嘌呤二核苷酸磷酸(NADH)和间接的谷胱甘肽的最重要细胞来源，将通过减少抗氧化保护和增强一氧化氮的氧化失活而导致血管功能障碍。项目2提出了中心假设，即G6PD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G6PD缺乏在心肌缺血-再灌注损伤中的作用，并评估在G6PD缺乏状态下增强抗氧化能力的潜在益处。项目4是该计划的一个新项目，将专注于一种假设，即心肌细胞中G6PD的耗竭将导致心肌细胞内活性氧生成增加，从而导致肥大、胎儿基因表达和细胞凋亡，这是不利的梗死后重塑的一个细胞机制。在项目5中，将进行人体研究，以检验G6PD缺乏症与血管中氧化应激增加以及伴随着动脉内皮细胞衍生的一氧化氮生物活性丧失有关的假设；重要的是，G6PD缺乏症将通过对每个被研究个体的特定活动测量和基因测序来确定。因此，随着这一广泛的方法围绕着一个发展良好和整合良好的心血管主题，这项针对黑人缺血性心脏病的SCOR应该继续提供机会，以确定关于黑人血管疾病的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.