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.
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