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.

中文翻译：

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褪黑素通过SIRT3依赖性调节氧化应激和细胞凋亡改善心肌缺血再灌注损伤

Sirtuins是一个高度进化保守的烟酰胺腺嘌呤核苷酸依赖性组蛋白脱乙酰基酶家族。Sirtuin-3（SIRT3）是sirtuin家族的成员，主要定位于线粒体，可预防氧化应激相关疾病，包括心肌缺血/再灌注（MI / R）损伤。褪黑激素在减轻MI / R损伤方面具有良好的作用。我们假设褪黑素可以通过激活SIRT3信号通路来预防MI / R损伤。在这项研究中，小鼠接受或不接受选择性SIRT3抑制剂预处理，然后进行MI / R手术。再灌注前10分钟腹膜内给予褪黑激素（20 mg / kg）。褪黑素治疗改善了缺血后心脏的收缩功能，减小了梗塞面积，减少了乳酸脱氢酶的释放，降低了细胞凋亡指数，并减轻了氧化损伤。值得注意的是，MI / R引起心肌SIRT3表达和活性的显着降低，而褪黑激素治疗则上调了SIRT3表达和活性，从而降低了超氧化物歧化酶2（SOD2）的乙酰化。此外，褪黑激素可响应MI / R而增加Bcl-2表达并降低Bax，Caspase-3和裂解Caspase-3的水平。但是，褪黑激素的心脏保护作用在很大程度上被选择性SIRT3抑制剂3-（1H-1,2,3-三唑-4-基）吡啶（3-TYP）所抵消，这表明SIRT3在介导心脏保护作用中起着至关重要的作用。褪黑激素的作用。体外研究证实，褪黑激素还可以通过减轻氧化应激和凋亡来保护H9c2细胞免受模拟的缺血/再灌注损伤（SIR）的侵害，而针对SIRT3的siRNA则可以减少这些影响。两者合计，我们的结果首次证明褪黑激素治疗通过激活SIRT3信号通路降低氧化应激和凋亡，从而改善了MI / R损伤。