褪黑素减轻心肌缺血/再灌注损伤的作用及机制

目的:探讨褪黑素（melatonin，Mel）在大鼠心肌缺血/再灌注（MI/R）损伤中的拮抗作用及其机制。方法:80只体质量200~250 g雄性SD大鼠随机分为4组:假手术（Sham）组、溶剂对照（MI/R+V）组、Mel治疗（MI/R+Mel）组、Mel+EX527（MI/R+Mel+EX）组。常规结扎左冠状动脉前降支行心肌缺血/再灌注手术，缺血30 min，再灌72 h后超声心动图法检测各组大鼠心功能，再灌6 h后ELISA法检测血清酶学指标，TUNEL法检测心肌细胞凋亡率，Evans blue-TTC双染法测定梗死面积，Western blot法检测沉默信息转录调控因子1（SIRT1）、乙酰化叉头转录因子1（Ac-Foxo1）及凋亡相关蛋白表达水平。结果:Mel治疗可显著改善MI/R损伤后心功能，降低血清肌酸激酶（CK）及乳酸脱氢酶（LDH）水平，降低凋亡率及梗死面积，上调SIRT1表达，下调Ac-Foxo1水平，降低凋亡相关蛋白表达。而使用EX527阻断SIRT1信号后逆转Mel的上述作用（均P<0.01）。结论:Mel可发挥抗凋亡作用减轻MI/R损伤并改善心功能，其作用机制可能与其激活SIRT1信号通路并降低Ac-Foxo1水平有关。

Protective effect of melatonin treatment against myocardial ischemia/reperfusion injury

AIM:To investigate the protective effect of melatonin (Mel) on myocardial ischemia/reperfusion (MI/R) injury and its underlying mechanisms. METHODS: Eighty male Sprague Dawley rats (200-250 g) were subjected to myocardial ischemia/reperfusion (MI/R, I 30 min, R 6 h) and randomly divided into four groups: MI/R+V (absolute alcohol diluted in sterile saline to 0.1 M, 1 ml/d, 7 d before MI/R; 1 ml/d, 15 min before reperfusion, ip), MI/R+Mel ［(10 mg/(kg·d), 7 d before MI/R; 15 mg/(kg·d), 15 min before reperfusion］, MI/R+Mel+EX ［Mel treatment following the same routine; EX527, 5 mg/(kg·d), every other day for three times; 5 mg/(kg·d), 20 min before reperfusion］ and sham (rats undergoing the same surgical procedures without tying the suture). Cardiac function 72 h after reperfusion, serum CK and LDH level, apoptotic index, infarct size, SIRT1 expression, Ac-Foxo1 expression and apoptosis related protein expression was detected. RESULTS: Seventy two h after MI/R operation, melatonin treatment group showed improved cardiac function, lower serum CK and LDH levels, decreased apoptotic index, decreased infarct size, upregulated SIRT1 expression, downregulated Ac-Foxo1 expression and decreased apoptosis related protein expression (all P<0.01). Moreover, SIRT1 inhibitor EX527 downregulated SIRT1 expression, upregulated Ac-Foxo1 expression and blocked the cardioprotective effect of melatonin. CONCLUSION: These data indicate that melatonin treatment attenuates myocardial ischemia/reperfusion injury by reducing apoptosis via a SIRT1 dependent signaling pathway.