Abstract
Exercise training is an effective, nonpharmacologic therapy and preventative measure for ischemic heart disease. While recent studies have examined reactive oxygen species (ROS) as mediators of exercise training-enhanced coronary blood flow, specific oxidants and their sources have yet to be fully elucidated. We investigated the hypothesis that NADPH oxidase (NOX)-derived superoxide anion would contribute to vasodilation effects in the coronary microcirculation of swine and that these effects would be impaired by chronic ischemia and rescued with exercise training. Adult Yucatan miniature swine were instrumented with an ameroid occluder around the proximal left circumflex coronary artery, resulting in a collateral-dependent myocardial region. Eight weeks post-operatively, swine were randomly assigned to either a sedentary or exercise training (treadmill run; 5 days/week for 14 weeks) protocol. Coronary arterioles were isolated from nonoccluded and collateral-dependent myocardial regions and pressure myography was performed. Exercise training resulted in enhanced endothelium-dependent dilation after occlusion. Scavenging of superoxide via the superoxide dismutase (SOD)-mimetic, tempol, attenuated dilation in both nonoccluded and collateral-dependent arterioles of exercise-trained, but not sedentary swine. NOX1/4 inhibition with GKT136901 attenuated dilation after exercise training but only in collateral-dependent arterioles. High performance liquid chromatography revealed that neither ischemia nor exercise training significantly altered basal or bradykinin-stimulated superoxide levels. Furthermore, superoxide production was not attributable to NOX isoforms nor mitochondria. Immunoblot analyses revealed significantly decreased NOX2 protein after exercise with no differences in NOX1, NOX4, p22phox, SOD proteins. Taken together, these data provide evidence that superoxide and NOX4 independently contribute to enhanced endothelium-dependent dilation following exercise training.
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