阿托伐他汀对糖尿病大鼠急性心肌梗死后心功能及HGF／c-Met 信号通路的影响

摘要

目的：糖尿病患者急性心肌梗死（ AMI）后的心室重构及心功能恶化较非糖尿病者更为明显。本研究旨在观察阿托伐他汀对糖尿病大鼠AMI后心肌细胞凋亡、心室重构及心功能的影响，并探讨其作用是否与肝细胞生长因子及其受体（HGF/c-Met）信号通路有关。方法：70只雄性SD大鼠经链脲霉素（STZ，65 mg/kg）腹腔注射，诱导糖尿病大鼠模型。8周后对糖尿病大鼠结扎左冠状动脉前降支构建AMI大鼠模型，术后存活32只大鼠随机分为2组：AMI对照组（n＝16）和阿托伐他汀干预组（n＝16，阿托伐他汀20 mg· kg-1· d-1），并在糖尿病大鼠中设假手术组（ n＝11），术后24 h予以灌胃给药。2周后比较各组大鼠心功能、心肌组织病理改变、心肌细胞凋亡、HGF和c-Met mRNA及蛋白表达差异。结果：（1） AMI对照组心功能显著低于假手术组（P＜0.05），胶原容积分数、心肌细胞凋亡指数、HGF及c-Met mRNA及蛋白表达均显著高于假手术组（ P＜0.05）；（2）阿托伐他汀干预组的胶原容积分数和心肌细胞凋亡指数显著低于AMI对照组（P＜0.05），心功能、HGF及c-Met mRNA及蛋白表达均显著高于AMI对照组（P＜0.05）。结论：阿托伐他汀对糖尿病大鼠AMI后心肌细胞凋亡、心室重构及心功能具有显著改善作用；HGF/c-Met信号通路在AMI后会激活，阿托伐他汀的上述作用机制可能与其进一步增强HGF/c-Met信号通路有关。%AIM:To investigate the effect of atorvastatin on myocardial apoptosis , ventricular remodeling and cardiac function after acute myocardial infarction (AMI) in diabetic rats, and to explore whether the effect is mediated by hepatocyte growth factor ( HGF)/c-Met signaling pathway .METHODS:Diabetes in 70 male SD rats was induced by in-traperitoneal injection of streptozotocin (STZ, 65 mg/kg).After 8 weeks, AMI was induced by the ligation of the left ante-rior descending coronary artery in the diabetic rats , and 32 surviving rats were divided into AMI group (n=16) and AMI+atorvastatin group ( n=16, 20 mg· kg -1 · d-1 ) at random.The similar surgical procedure was completed in sham group (n=11) without coronary ligation.Atorvastatin was given daily by gavage from the first day after AMI .Two weeks later, the cardiac function , pathological changes of myocardial tissues , myocardial apoptosis , and the expression of HGF and c-Met were compared among groups .RESULTS: AMI significantly reduced cardiac function , increased collagen volume fraction ( CVF) and myocardial apoptotic index , and up-regulated the expression of HGF and c-Met at mRNA and protein levels in AMI control group (P<0.05).The cardiac function was improved , and CVF and myocardial apoptotic index were reduced by the treatment with atorvastatin , which also up-regulated the expression of HGF and c-Met (P<0.05).CON-CLUSION:Atorvastatin significantly attenuates myocardial apoptosis and cardiac remodeling , and improves cardiac func-tion after AMI in diabetic rats by further enhancing the activation of HGF /c-Met pathway .