褪黑素抗心肌缺血/再灌注损伤的作用及其对Notch1/Hes1信号通路影响

目的 探讨褪黑素（melatonin，Mel）对减轻大鼠心肌缺血/再灌注（MI/R）损伤的作用及其对心肌Notch1/Hes1信号的影响。方法 90只雄性SD大鼠（200~250） g，随机分为3组（每组n=30）:假手术（Sham）组、溶剂对照（MI/R+V）组和Mel处理（MI/R+Mel）组〔10 mg/(kg·d)，灌胃4周〕。行结扎大鼠冠状动脉左前降支手术造成MI/R模型，心肌缺血30 min，再灌注4 h后检测心肌Notch1 受体胞内区（Notch1 intracellular domain,NICD）及Hes1、PTEN、p-Akt/Akt比值和凋亡相关蛋白表达，再灌注6 h后检测梗死面积和心肌细胞凋亡率，再灌注72 h后检测心功能。结果 MI/R损伤显著下调左心射血分数（LVEF）与左心室短轴缩短率（LVFS），增加心肌凋亡率及梗死面积。Mel口服预防性治疗4周可显著改善心功能并减轻心肌凋亡及梗死（P<0.01）。另外口服Mel治疗可显著激活心肌Notch1/Hes1信号通路并调控PTEN/Akt信号，从而下调心肌凋亡信号(P<0.05)。结论 口服Mel预防性治疗可显著减轻MI/R损伤后心肌梗死及凋亡水平，改善心功能。而且，Mel口服可显著上调缺血打击后心肌Notch1/Hes1信号并对PTEN/Akt信号发挥调控作用，下调心肌凋亡信号，从而保护心肌。

Melatonin protects against ischemia/reperfusion injury possibly through activating cardiac Notch1/Hes1 signaling

AIM To explore the protective action of melatonin (Mel) against myocardial ischemia/reperfusion (MI/R) injury and its association with myocardial Notch1/Hes1 signaling pathway. METHODSNinety male Sprague Dawley rats weighing 200-250 g were subjected to myocardial ischemia/reperfusion (MI/R, I 30 min, R 4 h) by occluding the left descending artery and were randomly divided into three groups: MI/R+V (absolute alcohol diluted in sterile saline to 0.1 M, 1 ml/day, 4 weeks), MI/R+Mel ［10 mg/(kg·day), 4 weeks before MI/R］ and sham (rats undergoing the same surgical procedures without tying the suture). After 4 h of reperfusion, myocardial NICD (Notch1 intracellular domain), Hes1, PTEN, p-Akt/Akt ratio and apoptotic related protein expressions were measured. After 6 h of reperfusion, myocardial apoptotic index and infarct size were evaluated. Cardiac functions were measured 72 h after reperfusion. RESULTSMel treatment significantly improved cardiac functional recovery and reduced myocardial apoptosis (P<0.01). Additionally, Mel treatment modulated PTEN/Akt signaling by activating Notch1/Hes1 signaling (P<0.05). CONCLUSIONOur results show that melatonin protects the heart against MI/R injury by reducing apoptosis, possibly through Notch1/Hes1 signaling pathway.