G6PD, OXIDATIVE STRESS AND NITRIC OXIDE INSUFFICIENCY

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The vascular diathesis of blacks is accompanied by increased oxidant stress and reduced bioavailable nitric acid. The resulting nitric oxide insufficiency state is largely a consequence of enhanced oxidative inactivation of nitric oxide by reactive oxygen species. A principal determinant of vascular cell defense against oxidative stress if the cell's ability to maintain reduced glutathione (GSH) stores through the synthesis of reduced nicotinamide adenine dinucleotide phosphate (NADPH). The primary enzyme responsible for maintaining NADPH concentrations is glucose-6-phosphate dehydrogenase (G6PD), which is the rate-limiting enzyme for the pentose phosphate pathway and coverts glucose-6-phosphate into 6-phosphoglucolactone, reducing NADP+ into NADPH in the process. NADPH, in turn, is a critical co-factor for the reduction of glutathione disulfide (GSSG) into GSH by glutathione reductase. Since GSH is required for the activity of glutathione peroxidase and NADPH is required for GSH synthesis, a deficiency of G6PD would be expected to limit a cell's ability to eliminate reactive oxygen intermediates in the form of peroxides, whose peroxyl derivatives can inactivate nitric oxide. Deficiency of G6PD is the most common enzymopathy worldwide, and highly prevalent among African Americans. The central hypothesis of this proposal is that G6PD deficiency enhances oxidant stress in the normal vasculature, leading to oxidative inactivation of nitric oxide and abnormal functional and adaptive vascular responses. To test this hypothesis, we propose to examine the effect of inhibiting G6PD activity or expression the susceptibility of endothelial or vascular smooth muscle cells to oxidant stress; to assess the antioxidant role of G6PD in endothelial or vascular smooth muscle cells by increasing its expression or availability; to study the role of G6PD on NO synthesis and oxidative metabolism; and to evaluate the role of G6PD on NO bioactivity in vascular cells and platelets using cell systems and animal models. These studies should provide new insights into the molecular mechanism(s) underlying the vascular diathesis of blacks, and may lead to unique therapeutic approaches for nitric oxide insufficiency states.