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Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT 3‐dependent regulation of oxidative stress and apoptosis
Author(s) -
Zhai Mengen,
Li Buying,
Duan Weixun,
Jing Lin,
Zhang Bin,
Zhang Meng,
Yu Liming,
Liu Zhenhua,
Yu Bo,
Ren Kai,
Gao Erhe,
Yang Yang,
Liang Hongliang,
Jin Zhenxiao,
Yu Shiqiang
Publication year - 2017
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12419
Subject(s) - melatonin , sirtuin 1 , oxidative stress , sirtuin , reperfusion injury , apoptosis , cardioprotection , endocrinology , medicine , ischemia , superoxide dismutase , sirt3 , pharmacology , biology , downregulation and upregulation , chemistry , nad+ kinase , biochemistry , enzyme , gene
Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide‐dependent histone deacetylases. Sirtuin‐3 ( SIRT 3) 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 SIRT 3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT 3 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 SIRT 3 expression and activity, whereas the melatonin treatment upregulated SIRT 3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 ( SOD 2). 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 SIRT 3 inhibitor 3‐(1H‐1,2,3‐triazol‐4‐yl)pyridine (3‐ TYP ), suggesting that SIRT 3 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 SIRT 3‐targeted si RNA 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 SIRT 3 signaling pathway.