苯扎贝特改善实验性糖尿病小鼠心肌肥厚作用及可能机制  

Protective effect of bezafibrate against experimental diabetic cardiac hypertrophy of mice and its possible mechanism

作　　者：张杰[1] 丁淑梅 邱红梅[1] 黄波 吴芹 蒋青松[1] ZHANG Jie;DING Shu-mei;QIU Hong-mei;HUANG Bo;WU Qin;JIANG Qing-song(Department of Pharmacology,Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology,Chongqing Medical University,Chongqing 400016,China;Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,Zunyi Medical University,Zunyi 563003,China)

机构地区：[1]重庆医科大学药理教研室,重庆市生物化学与分子药理学重点实验室,重庆400016 [2]遵义医学院基础药理教育部重点实验室暨特色民族药教育部国际合作联合实验室,贵州遵义563003

出　　处：《中国药理学与毒理学杂志》2018年第10期764-771,共8页Chinese Journal of Pharmacology and Toxicology

基　　金：贵州省遵义医学院基础药理学重点实验室开放基金项目(JCYL-K-007);重庆市自然科学基金(cstc2017jcjAX0211);贵州省中医药管理局项目(QZYY-2016-004);国家自然科学基金(NSFC81471334).

摘　　要：目的观察苯扎贝特(BEZ)对糖尿病小鼠心肌肥厚的治疗作用及其对环氧廿碳三烯酸(EET)的影响。方法小鼠高糖高脂饮食喂养4周后,连续5 d ip给予STZ 40 mg·kg^(-1),7 d后测量小鼠空腹血糖(FBG)值。随机选取FBG≥11.1 mmol·L^(-1)的小鼠,继续给予高糖高脂饮食4周后,分为模型组、BEZ 25 mg·kg^(-1)(约为临床常用剂量1/3)组和BEZ 75 mg·kg^(-1)(与临床常用剂量相当)组,ig给药,1次/d,持续4周。每周监测小鼠体质量(BM)及FBG。实验结束时,取血检测甘油三酯(TG)、总胆固醇(TCH)和14,15-EET含量。以心肌肥厚指数(LVHI)、左心室/体质量比(LV/BM)和心房肽(ANF)表达为心肌肥厚检测指标,HE和Masson染色观察左心室组织病理学改变。逆转录定量PCR和Western印迹法分别检测左心室心肌组织中ANF mRNA和细胞色素P450表氧化酶2J3(CYP2J3)蛋白表达。结果小鼠FBG持续≥11.1 mmol·L^(-1),提示糖尿病形成。4周后,糖尿病小鼠的LVHI,LV/BM和ANF mRNA表达增加(P<0.01),心肌结构损伤,出现心肌肥厚。实验结束时,TG和TCH含量增加(P<0.01);同时,左心室心肌组织CYP2J3表达下调,血清14,15-EET含量减少(P<0.01)。给予BEZ 25和75 mg·kg^(-1)治疗后,FBG均降低,TG和TCH亦减少(P<0.05);但只有BEZ 75 mg·kg^(-1)组小鼠心肌肥厚改善,CYP2J3表达和14,15-EET水平升高(P<0.05)。结论临床相当剂量的BEZ对糖尿病小鼠心肌肥厚有保护作用,该作用可能与CYP2J3-EET激活有关。OBJECTIVE To observe the protective effect of bezafibrate(BEZ) against cardiac hypertrophy in diabetic mice and explore its effect on epoxyeicosatrienoic acid(EET). METHODS A diabetic model was established by feeding mice a high-energy diet for 4 weeks combined with streptozotcin(STZ, 40 mg·kg^-1, ip) for 5 d. After 7 d, the fasting blood glucose(FBG) levels of the mice were assayed,and the mice with FBG≥11.1 mmol·L^-1 were kept on the high-energy diet for 4 weeks. Then, the mice were randomly divided to three groups: diabetic cardiac hypertrophy model group, BEZ 25 mg · kg^-1(about 1/3 of the clinically used dose) group and BEZ 75 mg·kg^-1(the clinically used dose) group. The mice were given the corresponding drug(ig) once a day for 4 weeks. The body mass(BM) and FBG of mice were monitored weekly. At the end of the experiment, blood was taken to detect the levels of triglycerides(TG), total cholesterol(TCH) and 14, 15-EET. Left ventricular hypertrophy was observed by left ventricular hypertrophy index(LVHI), left ventricular-to-body mass ratio(LV/BM), atrial natriuretic factor(ANF) mRNA expression and histopathology. qRT-PCR and Western blotting were used to detect ANF mRNA and cytochrome P450 2J3(CYP2J3) protein expression, respectively. RESULTS After 7 d of treatment with STZ, the FBG of mice exceeded 11.1 mmol·L^-1, which suggested that a diabetic model had been established. After 4 weeks, the increased levels of LVHI and LV/BW, ANF mRNA expression,surface area of myocardial cells and collagen volume fraction(P<0.01) suggested the occurrence of cardiac hypertrophy in diabetic mice. At the end of the experiment, cardiac hypertrophy was aggravated in diabetic mice, accompanied by the increase in TG and TCH(P<0.01). Meanwhile, the CYP2J3 expression and 14, 15-EET level were reduced in diabetic cardiac hypertrophy mice(P<0.01). After BEZ treatment at both 25 and 75 mg·kg^-1 for 4 weeks, the levels of FBG, TG and TCH decreased(P<0.05). However, the improved cardiac hypertrophy only appeared in diabetic mic

关 键 词：苯扎贝特 糖尿病 心肌肥厚 环氧廿碳三烯酸 细胞色素P450表氧化酶2J3 

分 类 号：R972.6[医药卫生—药品] R963[医药卫生—药学]