Exercise Training Shifts Dependency from NADPH Oxidase 2 to NADPH Oxidase 4 in EndotheliumDependent Dilation in Coronary Arterioles Distal to Chronic Occlusion
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Previously, we have reported that exercise training enhances endotheliumdependent dilation in coronary arterioles distal to chronic occlusion, through increased contribution of the redox signaling molecule, hydrogen peroxide (H2O2). In the present study, we tested the hypothesis that enhanced endotheliumdependent dilation in collateraldependent arterioles after exercise training would be attributable to an increased contribution of NADPH oxidase (NOX) 4derived reactive oxygen species. Yucatan miniature swine were surgically instrumented with an ameroid constrictor around the proximal left circumflex artery, which gradually induced occlusion of the artery and created a collateraldependent vascular bed. Eight weeks postoperatively, swine were assigned to either a sedentary protocol consisting of normal pen activity or a progressive exercisetraining regimen comprised of treadmill running 5 days a week, for 14 weeks. Coronary arterioles were isolated from the nonoccluded and collateraldependent myocardial regions and bradykininmediated dilation via pressure myography was performed in the presence and absence of ML171, gp91dstat and GKT136901, inhibiting NOX1, NOX2, and NOX1/4 isoforms, respectively. Additionally, using the superoxide probe, dihydroethidium, HPLC analysis was performed on isolated microvascular endothelial cells, pretreated with NOX inhibitors, to determine candidate sources of superoxide. Inhibition of NOX2 produced a significant rightward shift in EC50 values of arterioles from sedentary animals, independent of occlusion, as well as the nonoccluded arterioles of exercisetrained pigs. EC50 values of collateraldependent arterioles from exercisetrained swine were not significantly altered by NOX2 inhibition. Contrastingly, collateraldependent arterioles from exercisetrained swine exhibited a significant shift in EC50 values in the presence NOX1/4 inhibition, which was absent in other arteriole treatment groups. Importantly, NOX1 inhibition did not significantly shift EC50 values in any treatment group, suggesting responses to the NOX1/4 inhibitor, GKT136901, reflect the contribution of NOX4. Interestingly, microvascular endothelial cell superoxide levels were not different across arteriole treatment groups. Our present findings suggest that exercise training produces adaptations in collateraldependent arterioles that appear to shift dependence from NOX2 to NOX4derived reactive oxygen species for endotheliumdependent dilation. Taken together with our previous findings, our data support the assertion that enhanced dilation of collateraldependent arterioles after exercise training is driven by enhanced NOX4derived H2O2 levels.
