尼可地尔通过p38MAPK信号抑制糖尿病大鼠心肌血栓素蛋白-1表达  

Nicorandil Inhibits the Expression of Thrombospondin-1 in Myocardium of Diabetic Rats via p38MAPK Signal Pathway

作　　者：王海蓉[1] 宋文豪[1] 熊峰[1] 赵明明[1] 张琳[1] 干学东[1] 熊世熙[1] 王扬淦[1] 

机构地区：[1]武汉大学中南医院心内科,湖北武汉430071

出　　处：《武汉大学学报（医学版）》2016年第5期718-724,共7页Medical Journal of Wuhan University

基　　金：国家自然科学基金资助项目(编号:81270304);湖北省自然科学基金资助项目(编号:2013CFB246)

摘　　要：目的:检测ATP敏感的钾通道激活剂尼可地尔对实验性糖尿病大鼠的心肌纤维化的影响。方法:链脲佐菌素诱导的糖尿病SD大鼠,随机分为3组,一组作为对照,一组口服安慰剂,一组给予(10mg/kg)尼可地尔12周。实验结束后分别测量心功能等指标,并检测心肌组织血栓素蛋白(TSP)-1、胶原、血管紧张素Ⅱ(AngⅡ)、TGF-β1、磷酸化p38MAPK等指标的水平。结果:与对照组比较,糖尿病大鼠12周时左心室功能受损。糖尿病大鼠心肌组织AngⅡ、TSP-1高表达,心肌组织p38MAPK水平增高,心肌间质纤维化明显。尼可地尔处理过的糖尿病大鼠,左室功能以及心肌间质纤维化程度显著减轻,其心肌组织TSP-1mRNA和蛋白质表达与p38MAPK途径均下调。结论:TSP-1在糖尿病心肌纤维化发生机制中起重要作用,与p38MAPK途径激活以及后续TGFβ-1以及胶原过度表达密切相关。尼可地尔对糖尿病心肌纤维化有较好逆转作用,其机制与抑制p38途径以及纤维化过程有关。Objective：To examine whether nicorandil,an ATP-sensitive potassium channel opener,exhibits cardioprotective actions on the process of interstitial fibrosis in experimental diabetic rats.Methods：Sprague-Dawley rats were injected with streptozocin（STZ）for inducing diabetes,and diabetic rats were randomized and treated orally with placebo or 10mg/kg of nicorandil daily for12 weeks.Then together with unmanipulated age-matched rats,body,heart and the left ventricle（LV）weights were measured and the contents of thrombospondin-1（TSP-1）,collagens,AngiotensinⅡ（Ang Ⅱ）,transforming growth factor-β1（TGF-β1）,phosphorylated p38 MAPK in the myocardial tissues were determined.Results：As comparison with that in control rats,the serious impaired left ventricular function were observed through body weight,the cardiac and LV indexes in diabetic model group of rats.Furtherly the increased diabetes-related formation of AngⅡ,TSP-1were activated by the p38 MAPK signal,which contributes to the progression of cardiac fi-brosis.In contrast,treatment with nicorandil significantly reduced the development of fibrosis and preserved the function of LV compared with that in diabetic model group.Furthermore,treatment with nicorandil inhibited the hyperglycemia-induced TSP-1mRNA and protein through p38 MAPK transduction in the myocardial tissues.Conclusion：These results suggest that TSP-1is an important regulator of the pathogenesis of hyperglycemia-related cardiomyopathy in rats and treatment with nicorandil may ameliorate the development of hyperglycemia-related cardiac interstitial fibrosis through p38 MAPK signal.

关 键 词：糖尿病 血栓素蛋白-1 心肌细胞 尼可地尔 转化生长因子-Β1 

分 类 号：R542.2[医药卫生—心血管疾病]