P601Cardio-protective effects of exercise are abolished in pressure-overload following aortic constriction by increased eNOS uncoupling and oxidative stress

Purpose: Cardio-protective effects of physical exercise training are generally recognized. However, previously we demonstrated that the beneficial effects of exercise critically depend on the underlying cause of cardiac dysfunction and showed that unlike following myocardial infarction (MI), exercise did not improve but rather tended to aggravate cardiac dysfunction and remodeling following mild and severe pressure-overload induced by a trans-aortic constriction (TAC). The mechanism behind the etiology-dependent effects of exercise in cardiac disease remains unclear but we hypothesize that nitric oxide synthases (NOS) dependent regulation of the balance between nitric oxide and superoxide (O2•−) is critically involved. Methods: Mice were exposed to 8 weeks of voluntary wheel running exercise training (EX) or sedentary housing (SED) immediately following MI, TAC or sham (SH) surgery. At the end of the 8 weeks training period cardiac function was studied and mice were sacrificed for cardiac tissue analysis. O2•− was measured using lucigenin-enhanced chemiluminescence. NOS, NADPH and xanthine oxidase (XO)-dependent O2•− production were measured using the NOS inhibitor L-NAME; NADPH substrate and inhibitor VAS2870, and XO substrate and inhibitor oxypurinol. eNOS uncoupling was evaluated with western blot. Results: Cardiac dysfunction and pulmonary congestion were ameliorated by exercise in MI but not in TAC mice. Thus fractional shortening increased from 8±1% in MISED to 12±1% in MIEX (p