MnSOD protects against COX1‐mediated endothelial dysfunction in chronic heart failure

Endothelial function is impaired by oxidative stress in chronic heart failure (CHF). Mechanisms that protect against increases in oxidative stress in CHF are not unclear. We examined endothelial function in aorta in wild‐type mice (MnSOD +/+ ) and mice deficient in manganese superoxide dismutase (MnSOD +/− ) 12 weeks after ligation of the left cornary artery (LCA). LCA ligation produced similar size infarctions in MnSOD +/+ and MnSOD +/− mice. Maximal relaxation in response to acetylcholine was 78 ± 3% (mean ± SE) and 66 ± 8% in sham‐operated MnSOD +/+ and MnSOD +/− mice, respectively. Induction of CHF increased MnSOD expression ~1.7 fold in MnSOD +/+ mice, but not in MnSOD +/− mice. Maximal relaxation to acetylcholine was impaired in MnSOD +/+ mice (68 ± 4%), with greater impairments in endothelial function in MnSOD +/− mice with CHF (46 ± 5%). Incubation of vessel rings with Tempol did not improve vasorelaxation in response to acetylcholine. However, incubation with nonspecific cyclooxygenase (COX) inhibitor indomethacin or the COX1‐specific inhibitor valeryl salicylate significantly improved relaxation to acetylcholine in CHF mice (maximum relaxation = 74 ± 5% and 91 ±1%, respectivley). Collectively, these data identify a novel mechanism whereby chronic increases in mitochondrial‐mediated oxidative stress impair vascular function via a COX1‐mediated endothelium‐derived contracting factor in CHF.