Exercise protects against myocardial ischemia-reperfusion injury via stimulation of β3-adrenergic receptors and increased nitric oxide signaling: Role of nitrite and nitrosothiols

John W. Calvert, Marah E. Condit, Juan Pablo Aragón, Chad K. Nicholson, Bridgette F. Moody, Rebecca L. Hood, Amy L. Sindler, Susheel Gundewar, Douglas R. Seals, Lili A. Barouch, David J. Lefer

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Exercise training confers sustainable protection against ischemia-reperfusion injury in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise protects the heart, but it is apparent that endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) play a role. Objective: To determine the role of β3-adrenergic receptors (β3-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise. Methods and results: Here we show that voluntary exercise reduces myocardial injury in mice following a 4-week training period and that these protective effects can be sustained for at least 1 week following the cessation of the training. The sustained cardioprotective effects of exercise are mediated by alterations in the phosphorylation status of eNOS (increase in serine 1177 and decrease in threonine 495), leading to an increase in NO generation and storage of NO metabolites (nitrite and nitrosothiols) in the heart. Further evidence revealed that the alterations in eNOS phosphorylation status and NO generation were mediated by β3-AR stimulation and that in response to exercise a deficiency of β3-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury. Conclusions: Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia-reperfusion injury by stimulation of β3-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols).

Original languageEnglish (US)
Pages (from-to)1448-1458
Number of pages11
JournalCirculation research
Volume108
Issue number12
DOIs
StatePublished - Jun 10 2011

Keywords

  • cardioprotection
  • exercise
  • nitric oxide
  • nitrite
  • nitrosothiol
  • β3-adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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