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MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure.

ABSTRACT: Endothelial function is impaired by oxidative stress in chronic heart failure (HF). Mechanisms that protect against increases in oxidative stress in HF are not clear. The goal of this study was to determine whether manganese superoxide dismutase (MnSOD) plays a key role in protecting against endothelial dysfunction in HF. Endothelial function and gene expression were examined in aorta from wild-type mice (MnSOD(+/+)) and mice deficient in MnSOD (MnSOD(+/-)) 12 wk after ligation of the left coronary artery (LCA). LCA ligation produced similar size myocardial infarctions in MnSOD(+/+) and MnSOD(+/-) mice and reduced ejection fraction to approximately 20% in both groups. Maximal relaxation in response to acetylcholine was 78 +/- 3% (mean +/- SE) and 66 +/- 8% in sham-operated MnSOD(+/+) and MnSOD(+/-) mice, respectively. Expression of antioxidant enzymes increased in MnSOD(+/+) mice with HF, and maximal relaxation to acetylcholine was slightly impaired (68 +/- 4%). Greater endothelial dysfunction was observed in MnSOD(+/-) mice with HF (46 +/- 5%, P < 0.05), which was significantly improved by polyethylene glycol-catalase but not Tempol. Incubation with the nonspecific cyclooxygenase (COX) inhibitor indomethacin or the COX1 inhibitor valeryl salicylate, but not the COX-2 inhibitor NS-398, significantly improved relaxation to acetylcholine in HF mice (maximum relaxation = 74 +/- 5, 91 +/- 1, and 58 +/- 5%). These data suggest that MnSOD plays a key role in protecting against endothelial dysfunction in HF. A novel mechanism was identified whereby chronic increases in oxidative stress, produced by mitochondrial SOD deficiency, impair vascular function via a hydrogen peroxide-dependent, COX1-dependent, endothelium-derived contracting factor.

SUBMITTER: Miller JD

PROVIDER: S-EPMC2867433 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

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MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure.

Miller Jordan D JD Peotta Veronica A VA Chu Yi Y Weiss Robert M RM Zimmerman Kathy K Brooks Robert M RM Heistad Donald D DD

American journal of physiology. Heart and circulatory physiology 20100319 5

Endothelial function is impaired by oxidative stress in chronic heart failure (HF). Mechanisms that protect against increases in oxidative stress in HF are not clear. The goal of this study was to determine whether manganese superoxide dismutase (MnSOD) plays a key role in protecting against endothelial dysfunction in HF. Endothelial function and gene expression were examined in aorta from wild-type mice (MnSOD(+/+)) and mice deficient in MnSOD (MnSOD(+/-)) 12 wk after ligation of the left coron ...[more]

PMID: 20304815

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Project description:Diabetes is associated with coronary endothelial dysfunction. Persistent oxidative stress during diabetes contributes to coronary endothelial dysfunction. The mitochondria are main sources of reactive oxygen species (ROS) in diabetes, and mitochondria-targeted antioxidant mito-Tempo can prevent mitochondrial reactive oxygen species (mROS) generation in a variety of disorders. Inhibition/inactivation of small-conductance Ca2+-activated K+ (SK) channels contribute to diabetic downregulation of coronary endothelial function/relaxation. However, few investigated the role of mROS on endothelial dysfunction/vasodilation and endothelial SK channel downregulation in diabetes. The aim of present study was to investigate the chronic administration of mito-Tempo, on coronary vasodilation, and endothelial SK channel activity of mice with or without diabetes. Mito-Tempo (1 mg/kg/day) was applied to the mice with or without diabetes (n = 10/group) for 4 weeks. In vitro relaxation response of pre-contracted arteries was examined in the presence or absence of the vasodilatory agents. SK channel currents of the isolated mouse heart endothelial cells were measured using whole-cell patch clamp methods. At baseline, coronary endothelium-dependent relaxation responses to ADP and the selective SK channel activator NS309 and endothelial SK channel currents were decreased in diabetic mice compared with that in non-diabetic (ND) mice (p < 0.05). After a 4-week treatment with mito-Tempo, coronary endothelium-dependent relaxation response to ADP or NS309 and endothelial SK channel currents in the diabetic mice was significantly improved when compared with that in untreated diabetic mice (p < 0.05). Interestingly, coronary relaxation responses to ADP and NS309 and endothelial SK channel currents were not significantly changed in ND mice after mito-Tempo treatment, as compared to that of untreated control group. Chronic inhibition of endothelial mROS appears to improve coronary endothelial function/dilation and SK channel activity in diabetes, and mROS inhibitors may be a novel strategy to treat vascular complications in diabetes.

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MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure.

Publications

MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure.

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