Glucose-6-phosphate dehydrogenase deficiency promotes endothelial oxidant stress and decreases endothelial nitric oxide bioavailability

The vascular endothelium compensates for oxidant stress by increasing the a ctivity of antioxidant enzymes such as glucose-6-phophate dehydrogenase (G6 PD). G6PD provides reducing equivalents of NAPDH to maintain glutathione st ores and modulates nitric oxide synthase (eNOS) activity. To determine whet her deficient G6PD activity perturbs these responses, we treated bovine aor tic endothelial cells with dehydroepiandrosterone or an antisense oligodeox ynucleotide to G6PD mRNA to decrease G6PD activity and expression. When exp osed to hydrogen peroxide, reactive oxygen species (ROS) accumulation was i ncreased in G6PD-deficient cells compared with those with normal activity. To determine the source of increased oxidant stress in G6PD-deficient cells , we used inhibitors of ROS generation, which suggested that eNOS was contr ibuting to ROS production. Treatment with L-NMMA, an inhibitor of eNOS medi ated-nitric oxide (NO) but not superoxide, production confirmed this observ ation; in contrast to L-NAME, L-NMMA promoted ROS generation in G6PD-defici ent cells. In addition, deficient G6PD activity was associated with a decre ase in endothelium-derived bioavailable NO in response to the agonists A231 87 and bradykinin as demonstrated by decreased endothelial cGMP and nitrate /nitrite levels. Enhanced ROS accumulation and decreased NO bioavailability may represent one mechanism by which G6PD deficiency contributes to vascul ar oxidant stress and endothelial dysfunction.