Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis.

Abstract

Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide-dependent histone deacetylases. Sirtuin-3 (SIRT3) is a member of the sirtuin family that is localized primarily to the mitochondria and protects against oxidative stress-related diseases, including myocardial ischemia/reperfusion (MI/R) injury. Melatonin has a favorable effect in ameliorating MI/R injury. We hypothesized that melatonin protects against MI/R injury by activating the SIRT3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT3 inhibitor and then subjected to MI/R operation. Melatonin was administered intraperitoneally (20 mg/kg) 10 minutes before reperfusion. Melatonin treatment improved postischemic cardiac contractile function, decreased infarct size, diminished lactate dehydrogenase release, reduced the apoptotic index, and ameliorated oxidative damage. Notably, MI/R induced a significant decrease in myocardial SIRT3 expression and activity, whereas the melatonin treatment upregulated SIRT3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 (SOD2). In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R. However, the cardioprotective effects of melatonin were largely abolished by the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), suggesting that SIRT3 plays an essential role in mediating the cardioprotective effects of melatonin. In vitro studies confirmed that melatonin also protected H9c2 cells against simulated ischemia/reperfusion injury (SIR) by attenuating oxidative stress and apoptosis, while SIRT3-targeted siRNA diminished these effects. Taken together, our results demonstrate for the first time that melatonin treatment ameliorates MI/R injury by reducing oxidative stress and apoptosis via activating the SIRT3 signaling pathway.

• Authors: Mengen Zhai, Buying Li, Weixun Duan, Lin Jing, Bin Zhang, Meng Zhang, Liming Yu, Zhenhua Liu, Bo Yu, Kai Ren, Erhe Gao, Yang Yang, Hongliang Liang, Zhenxiao Jin, Shiqiang Yu
• Journal: Journal of pineal research (J Pineal Res) Vol. 63 Issue 2 (Sep 2017) ISSN: 1600-079X [Electronic] England
• PMID: 28500761 (Publication Type: Journal Article)
• Copyright: © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Bax protein, mouse
• Sirt3 protein, mouse
• bcl-2-Associated X Protein
• Superoxide Dismutase
• superoxide dismutase 2
• Casp3 protein, mouse
• Caspase 3
• Sirtuin 3
• Melatonin

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Male
• Melatonin (pharmacology)
• Mice
• Myocardial Reperfusion Injury (drug therapy, metabolism, pathology)
• Oxidative Stress (drug effects)
• Signal Transduction (drug effects)
• Sirtuin 3 (metabolism)
• Superoxide Dismutase (metabolism)
• bcl-2-Associated X Protein (metabolism)