抗糖尿病心肌缺血/再灌注损伤新机制：褪黑素膜受体-PKGIα-SIRT1介导褪黑素心脏保护作用的关键信号通路研究

线粒体功能障碍加重糖尿病心肌缺血/再灌注损伤（MI/RI），临床缺乏有效干预策略。我们发现褪黑素可维护心肌线粒体功能、减轻糖尿病MI/RI，且褪黑素膜受体及下游cGMP-PKGIα通路可能介导此作用，但参与此过程的褪黑素受体具体亚型及确切机制尚无报道，限制褪黑素临床应用。沉默信息调控因子1（SIRT1）对心肌线粒体功能发挥重要调节作用且SIRT1细胞核转位是其发挥细胞保护作用的关键过程。我们预实验发现褪黑素可促进糖尿病缺血心肌SIRT1核转位，而褪黑素膜受体拮抗剂抑制此作用，提示活化褪黑素膜受体及下游PKGIα通路很可能是激动SIRT1信号进而维护糖尿病心肌线粒体功能的关键机制。本项目拟利用心肌特异性SIRT1基因敲除小鼠和褪黑素膜受体基因敲除小鼠，在细胞与在体水平阐明褪黑素膜受体介导褪黑素抗糖尿病MI/RI的详细机制，为其临床试验提供理论依据，为防治糖尿病心肌缺血损伤提供新策略和新靶点。

Mitochondrial dysfunction in diabetic state aggravates myocardial ischemia/reperfusion injury (MI/RI). However, there is still a lack of effective therapeutic strategy. We previously found that melatonin could preserve myocardial mitochondrial function and reduce MI/RI in diabetic state, while melatonin membrane receptors and its downstream cGMP-PKGIα signaling pathway might mediate this effect. However, the specific type of melatonin receptor involved in this process and the detailed mechanisms have not been reported previously, which severely limit the further clinical application of melatonin. Silent information regulator 1 (SIRT1) plays an important role in the regulation of myocardial mitochondrial function and the nuclear translocation of SIRT1 is a critical process for its cytoprotective actions. The result of our pre-experiment showed that melatonin could promote SIRT1 nuclear translocation in diabetic ischemic myocardium, while the melatonin receptor antagonist inhibited this effect, suggesting that activation of melatonin membrane receptor and its downstream PKGIα pathway is likely to activate the SIRT1 signaling, thus preserving the myocardial mitochondrial function. The aim of this study was to elucidate the mechanisms of melatonin against diabetic MI/RI in the in vitro and in vivo settings by employing cardiac-specific SIRT1 knockout mice and melatonin membrane receptor knockout mice. This study will not only provide a theory for further clinical trials, but also provide new strategies and new targets for the prevention and treatment of diabetic myocardial ischemic injury.