间歇性低氧干预对心肌梗死大鼠AMPKα1/SIRT3通路及心肌能量代谢的影响

Intermittent hypoxia can improve myocardial energy metabolism

目的探讨间歇性低氧(IH)干预对心肌梗死(MI)大鼠心肌能量代谢的影响及可能作用机制。方法采用随机数字表法将21只SD大鼠分为假手术组、心梗组及观察组,将心梗组及观察组大鼠制成左冠状动脉前降支(LAD)闭塞心肌梗死模型。于造模结束1周后假手术组及心梗组大鼠均给予常氧干预,观察组大鼠则给予4周(4 h/d,5 d/周)间歇性低氧干预。于造模后1周、IH干预4周后检测各组大鼠左心室射血分数(LVEF);于IH干预4周后检测各组大鼠心肌纤维化指数、线粒体结构、ATP含量、腺苷酸活化蛋白激酶(AMPKα1)及Sirtuins蛋白家族成员3(SIRT3)蛋白表达水平。结果经IH干预4周后与假手术组比较,心梗组LVEF、线粒体数量、ATP含量、AMPKα1及SIRT3蛋白表达均明显降低(P<0.05),心肌纤维化指数明显增加(P<0.05);观察组LVEF明显降低(P<0.05),心肌纤维化指数明显增加(P<0.05),线粒体数量、ATP含量、AMPKα1及SIRT3蛋白表达组间差异均无统计学意义(P>0.05)。与心梗组比较,观察组LVEF、线粒体数量、ATP含量、AMPKα1及SIRT3蛋白表达均显著增加(P<0.05),心肌纤维化指数明显降低(P<0.05)。相关性分析显示大鼠心肌AMPKα1、SIRT3蛋白表达均与LVEF、ATP含量呈正相关(P<0.05),AMPKα1与SIRT3亦具有正相关性(P<0.05)。结论IH干预可通过调控MI大鼠AMPKα1/SIRT3通路促进心肌ATP合成,改善线粒体结构完整性,进而抑制心肌纤维化、增强心功能。

Objective:To explore any effect of intermittent hypoxia(IH)on myocardial energy metabolism and its mechanism.Methods:Twenty-one male Sprague-Dawley rats were randomly divided into a sham operation group,a myocardial infarction group and an observation group.The latter two groups received occlusion of the left anterior descending coronary artery.The observation group then lived in an hypoxic environment intermittently for 4 hours/day,5 days/week for four weeks,while the other 2 groups were exposed to a normal level of oxygen.The ejection fraction of the left ventricle(LVEF)was measured at 1 week after the modeling and 4 weeks after the start of the intervention.Also at that point myocardial fibrosis,mitochondrial structure,ATP content,and the protein expressions of adenosine monophosphate-activated protein kinase alpha1(AMPKα1)and sirtuins protein family member 3(SIRT3)were assessed in all three groups.Results:A significant decrease in the LVEF,the number of mitochondria,ATP content,AMPKα1 and SIRT3 protein were observed in the infarction group compared with the sham group.There was also a significant increase in the myocardial fibrosis index.Moreover,the LVEF decreased significantly and the myocardial fibrosis index had increased significantly in the observation group compared with the sham operation group,though the two groups exhibited no significant differences the number of mitochondria,ATP content,or the expression of AMPKα1 or SIRT3.Compared with the myocardial infarction group,in the observation group there was a significant increase in the LVEF,the number of mitochondria,ATP content,and the expression of AMPKα1 and SIRT3 protein,with a significant decrease in the fibrosis index.AMPKα1 and SIRT3 level were positively inter-correlated and positively correlated with LVEF and ATP content.Conclusions:IH intervention can promote ATP synthesis and improve mitochondrial structure by regulating the AMPKα1/SIRT3 pathway,reducing myocardial fibrosis and enhancing cardiac function.