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

  • J Pineal Res. 2017 Sep;63(2). doi: 10.1111/jpi.12419.
Mengen Zhai  1 ,  Buying Li  1 ,  Weixun Duan  1 ,  Lin Jing  2 ,  Bin Zhang  1 ,  Meng Zhang  3 ,  Liming Yu  4 ,  Zhenhua Liu  1 ,  Bo Yu  1 ,  Kai Ren  1 ,  Erhe Gao  5 ,  Yang Yang  6 ,  Hongliang Liang  1 ,  Zhenxiao Jin  1 ,  Shiqiang Yu  1
Affiliations
  • 1. Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
  • 2. Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer, The Fourth Military Medical University, Xi'an, China.
  • 3. Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
  • 4. Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, China.
  • 5. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
  • 6. Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China.
PMID: 28500761 DOI: 10.1111/jpi.12419
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.

Keywords
apoptosis; melatonin; myocardial ischemia reperfusion injury; oxidative stress; sirtuin-3.
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