Journal
CIRCULATION RESEARCH
Volume 108, Issue 12, Pages 1448-U125Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.241117
Keywords
beta(3)-adrenergic receptor; nitric oxide; cardioprotection; exercise; nitrite; nitrosothiol
Funding
- American Diabetes Association [7-09-BS-26, 1-10-BS-11]
- American Heart Association [09BGIA2250379]
- National Institutes of Health National Heart Lung and Blood Institute (NHLBI) [5R01HL-092141-02, 1R01HL093579-01, 1R01HL098481-01]
- Carlyle Fraser Heart Center (CFHC) of Emory University Hospital Midtown
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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 beta(3)-adrenergic receptors (beta(3)-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 beta(3)-AR stimulation and that in response to exercise a deficiency of beta(3)-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 beta(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols). (Circ Res. 2011;108:1448-1458.)
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