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 ( 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.