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

Jordan D. Miller, Veronica A. Peotta, Yi Chu, Robert M. Weiss, Kathy Zimmerman, Robert M. Brooks, Donald D. Heistad

Research output: Contribution to journalArticle

29 Scopus citations

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 ∼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.

Original languageEnglish (US)
Pages (from-to)H1600-H1607
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • Cyclooxygenase
  • Endothelium
  • Endothelium-derived contracting factor
  • Mitochondria
  • Oxidative stress
  • Vasomotor function

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Miller, J. D., Peotta, V. A., Chu, Y., Weiss, R. M., Zimmerman, K., Brooks, R. M., & Heistad, D. D. (2010). MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure. American Journal of Physiology - Heart and Circulatory Physiology, 298(5), H1600-H1607. https://doi.org/10.1152/ajpheart.01108.2009