摘要
目的探究动力相关蛋白(Dynamin-related protein,Drp)1抑制剂Mdivi-1对糖尿病小鼠心肌缺血/再灌注(Myocardial ischemia/reperfusion,MI/R)损伤的作用及其机制。方法高脂饮食加小剂量链脲佐菌素(STZ)诱导建立糖尿病小鼠模型。造模成功的糖尿病小鼠进行MI/R处理,再灌注前15 min腹腔注射Mdivi-1(1.2 mg/kg)或其溶剂二甲基亚砜。主要评价指标包括线粒体形态、心脏功能、心肌损伤及凋亡,蛋白免疫印迹检测Drp1表达。结果糖尿病MI/R后线粒体分裂增加(P<0.01),线粒体Drp1转位明显增加(P<0.01),Mdivi-1可抑制缺血/再灌注心肌的Drp1线粒体转位及线粒体分裂,减少心肌梗死面积和心肌细胞凋亡(P<0.01),减轻氧化应激(P<0.05)。结论 Drp1介导的线粒体分裂增加参与了糖尿病MI/R损伤,Drp1抑制剂Mdivi-1可抑制线粒体分裂,减轻糖尿病MI/R损伤。
AIM To investigate the effects of Mdivi-1, a small molecule inhibitor of dynamin-related protein 1 （Drp1）, on myocardial ischemia-reperfusion injury in diabetic mice. METHODS High-fat diet and streptozotocin-induced diabetic mice were subjected to myocardial ischemia-reperfusion （MI/R） or sham operation. Mdivi-1 （1.2 mg/kg） or vehicle （dimethyl sulfoxide） was administrated to the mice 15 min before the onset of reperfusion by intraperitoneal injection. Outcome measures included mitochondrial morphology, cardiac functions, myocardial injury and apoptosis. The expression of Drp1 was analyzed by Western blot. RESULTS Enhanced mitochondrial fission and increased mitochondrial Drp1 translocation were induced by I/R in diabetic hearts. Delivery of Mdivi-1 into diabetic mice markedly inhibited Drp1 translocation to the mitochondria and reduced mitochondrial fission following MI/R. Inhibition of Drp1 reduced myocardial infarct size, inhibited cardiomyocyte apoptosis and alleviated oxidative stress in diabetic MI/R mice. CONCLUSION Drp1-mediated mitochondrial fission is involved in diabetic MI/R injury. Pharmacological inhibition of Drp1 with Mdivi-1 prevents mitochondrial fission and reduces I/R injury in diabetic mouse hearts.
作者
刘铮
刘振华
贾敏
冯嘉豪
李泽阳
丁铭格
付锋
LIU Zheng;LIU Zhen-hua;JIA Min;FENG Jia-hao;LI Ze-yang;DING Ming-ge;FU Feng(First Cadet Brigade;Department of Physiology, Fourth Military Medical University, Xi＇an 710032, Shaanxi, China;Department of Geriatrics, Xi＇an Central Hospital, Xi＇an 710005, Shaanxi, China)
出处
《心脏杂志》
CAS
2018年第4期378-382,共5页
Chinese Heart Journal
基金
国家自然科学基金项目资助(81670354
81600235)
关键词
动力相关蛋白
线粒体分裂
糖尿病
心肌缺血/再灌注
氧化应激
dynamin-related protein 1
mitochondrial fission
diabetesl
myocardial ischemia-reperfusion
oxidative stress
