曲美他嗪对糖尿病心肌梗死大鼠心室重构及葡萄糖转运蛋白影响的实验研究

Effects of Trimetazidine on ventricular remodeling and GLUT4 in diabetic rats after myocardial infarction

目的观察糖尿病合并心肌梗死大鼠心脏结构、功能变化和葡萄糖转运蛋白4（GLUT4）表达及曲美他嗪对其影响。方法高脂高糖喂养大鼠6周腹腔注射链脲佐菌素建立2型糖尿病模型后结扎冠状动脉左前降支建立2型糖尿病合并心肌梗死模型。术后24h存活大鼠随机分为安慰剂组和曲美他嗪组；另设糖尿病假手术组。正常喂养大鼠同样以结扎冠状动脉方法制备心肌梗死模型后设立非糖尿病心肌梗死组；并设非糖尿病假手术组。曲美他嗪组以30mg·kg^-1·d^-1灌胃给药，其余各组灌以等量饮用水。6周后行心脏超声和血流动力学检查，计算心室重量指数（VWI），并进行心肌梗死面积及左室非梗死区心肌胶原容积分数（CVF）测定。取大鼠远离梗死区心肌，采用荧光定量RT—PCR技术测定GLUT4 mRNA，Western印迹测定GLUT4蛋白表达。结果糖尿病合并心肌梗死后6周时，与糖尿病假手术组以及非糖尿病心肌梗死组比较，糖尿病合并心肌梗死组左室舒张末期内径（LVDd）增大，左室收缩及舒张功能减低，VWI和CVF亦增大。与安慰剂组比较，曲美他嗪组左室舒张功能改善，二尖瓣口血流流速（E／A）比值减小[（4．7±1．7比6．8±1．6，P〈0．05）；CVF值减小（3．9±0．2）％比（6．3±0．4）％，P〈0．05）]，LVDd、VWI和左室收缩功能变化不显著。糖尿病合并心肌梗死组GLUT4 mRNA及蛋白表达下降。曲美他嗪组GLUT4表达增加。结论曲美他嗪可以改善糖尿病合并心肌梗死大鼠左室舒张功能。可通过增加GLUT4表达，抑制心肌纤维化。

Objective The aim of study is to investigate the changes of structure and function of heart in diabetic rat after myocardial infarction, and to study the expression of the GLUT4 and the effects of trimetazidine on the ventricular remodeling. Methods Type 2 diabetes rat was made by feeding with a diet enriched with sucrose, fat and cholesterol for six weeks and then injecting streptozotion intraperitoneally, then the myocardial infarction by ligating coronary artery. The living rats were randomly divided into three groups twenty-four hours after operation： placebo; trimezidine and sham operated with diabetes. And other rats which was fed with normal diet were divided into myocardial infarction group without diabetes and sham operated group without diabete. The treat group was intragastric administrated with trimetazidine which was solved in distilled water （30 mg · kg^-1 1 · d^-1 ）, and others were poured with partes aequales distilled water. After six weeks, echocardiographic and hemodynamic studies were performed, ventriculars were weighed, myocardial infarct size and myocardial collagen volume fraction（CVF） of non-infarction area were detected also. GLUT4 mRNA in the myocardium away from infarction region were measured with fluorescent quantitation RT-PCR and GLUT4 protein were measured with Western blot. Results Six weeks after diabetes complicating with myocardial infarction, comparing with sham operated group without diabete, diabetes sham operated group and myocardial infarction group without diabete, LVDd of diabetes complicating with myocardial infarction group was increased significantly; the systolic and diastolic function with left ventricular were decreased significantly , VWI and CVF were increased significantly; comparing with placebo group, diastolic function of left ventricular in trimetazidine group was improved significantly （4. 7 ± 1.7 vs 6.8 ± 1.6,P 〈0.05）; CVF（3.9 ±0.2）% vs （6.3 ±0.4）%,（P 〈0.05） was decreased significantly , but LVDd, VWI and the systolic function was not chang significantly. The expression ofGLUT4 mRNA and protein in sham operated with diabetes and diabetic with myocardial infarction descended significantly compared with sham operated group without diabete （ P 〈 0. 01 ）. And in trimezidine group, GLUT4 protein moderately increased （P 〈 0. 05 ） compared with placebo group. Conclusion Trimetazidine could improve the diastolic function of left ventricular. The expression of GLUT4 mRNA and protein in type 2 diabetes complicating with myocardial infarction decreased. Trimetazidine could improve the expression of GLUT4 mRNA and protein in diabetes complicating with myocardial infarction and inhibite myocardial fibrosis.