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Exercise protects against myocardial ischemia-reperfusion injury via stimulation of ?(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols.

ABSTRACT: 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.To determine the role of ?(3)-adrenergic receptors (?(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise.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 ?(3)-AR stimulation and that in response to exercise a deficiency of ?(3)-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury.Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia-reperfusion injury by stimulation of ?(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols).

SUBMITTER: Calvert JW

PROVIDER: S-EPMC3140870 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Exercise protects against myocardial ischemia-reperfusion injury via stimulation of β(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols.

Calvert John W JW Condit Marah E ME Aragón Juan Pablo JP Nicholson Chad K CK Moody Bridgette F BF Hood Rebecca L RL Sindler Amy L AL Gundewar Susheel S Seals Douglas R DR Barouch Lili A LA Lefer David J DJ

Circulation research 20110428 12

<h4>Rationale</h4>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.<h4>Objective</h4>To determine the role of β(3)-adrenergic receptors (β(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) ...[more]

PMID: 21527738

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Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

Dataset Information

Exercise protects against myocardial ischemia-reperfusion injury via stimulation of ?(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols.

Publications

Exercise protects against myocardial ischemia-reperfusion injury via stimulation of β(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols.

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