Ischemic heart disease in blacks is associated with hypertension, left ventricular hypertrophy, microvascular dysfunction, and an overall worse outcome compared to whites. In the first cycle of this SCOR program, we demonstrated that this black vascular diathesis is associated with an impairment of nitric oxide (NO) action, which was related to increased oxidative stress. African Americans have a high prevalence of glucose-6- phosphate dehydrogenase (G6PD) deficiency compared to whites and this enzyme plays a central role in regulating the antioxidant protection in the cell. Specifically, G6PD produces nicotinamide adenine dinucleotide phosphate (NADPH), which is important for the activity of a number of key enzymes including glutathione reductase, catalase, NO synthase, and indirectly glutathione peroxidase. Although the importance of G6PD activity for erythrocyte susceptibility to oxidant-induced hemolysis has long been recognized, the vascular consequences of this deficiency have not been well studied. Preliminary data presented in this application demonstrate an impairment of NO action and increased levels of 8-epi- PGF/2alpha, a marker of systemic lipid peroxidation, in patients with G6PD deficiency. On the basis of these results, we hypothesize that G6PD deficiency in African Americans is associated with increased oxidative stress in the vasculature leading to impaired NO action and contributing to the black vascular diathesis. We will test this hypotheses in four specific aims: 1) to examine the impact of G6PD deficiency (assessed biochemically), on NO-dependent vasodilation in the brachial and coronary circulations in 400 normotensive and hypertensive blacks, 2) to characterize G6PD deficiency on a molecular basis and relate specific G6PD mutations to vascular function in blacks, 3). To examine the vascular consequences of G6PD deficiency. These studies will provide insights to the pathophysiology of ischemic heart disease in blacks and will likely lead to improved patient management.
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