Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training

The bioactivity of endothelium-derived nitric oxide (NO) reflects its rates of production and of inactivation by superoxide (O-2(.-)), a reactive spec ies dismutated by extracellular superoxide dismutase (ecSOD). We have now e xamined the complementary hypothesis, namely that NO modulates ecSOD expres sion. The NO donor DETA-NO increased ecSOD expression in a time- and dose-d ependent manner in human aortic smooth muscle cells. This effect was preven ted by the guanylate cyclase inhibitor ODQ and by the protein kinase G (PKG ) inhibitor Rp-8-CPT-cGMP. Expression of ecSOD was also increased by 8-brom o-cGMP, but not by 8-bromo-cAMP. Interestingly, the effect of NO on ecSOD e xpression was prevented by inhibition of the MAP kinase p38 but not of the MAP kinase kinase p42/44, suggesting that NO modulates ecSOD expression via cGMP/PKG and p38MAP kinase-dependent pathways, but not through p42/44MAP k inase. In aortas from mice lacking the endothelial nitric oxide synthase (e NOS), ecSOD was reduced more than twofold compared to controls. Treadmill e xercise training increased eNOS and ecSOD expression in wild-type mice but had no effect on ecSOD expression in mice lacking eNOS, suggesting that thi s effect of exercise is meditated by endothelium-derived NO. Upregulation o f ecSOD expression by NO may represent an important feed-forward mechanism whereby endothelial NO stimulates ecSOD expression in adjacent smooth muscl e cells, thus preventing O-2(.-)-mediated degradation of NO as it traverses between the two cell types.