曲美他嗪对糖尿病大鼠心肌细胞氧化应激和内质网应激水平的影响

Effect of trimetazidine on the oxidative and endoplasmic reticulum stress levels of cardiomyocytes in diabetic rats

目的建立糖尿病大鼠动物模型,探讨曲美他嗪对糖尿病大鼠心肌组织氧化应激水平和内质网应激水平的影响。方法将30只健康雄性SD大鼠随机平均分为对照组(C组)、糖尿病组(DM组)、糖尿病+曲美他嗪治疗组(TDM组)。C组予标准饲料;DM组和TDM组予高脂饲料,喂养4周后一次性腹腔注射链脲佐菌素(30 mg/kg);TDM组予曲美他嗪(20 mg·kg^(-1)·d^(-1))灌胃,C组和DM组予等量盐水灌胃,持续4周。观察曲美他嗪对糖尿病心肌损伤的影响。通过免疫组织化学染色和Western blotting检测各组心肌组织中氧化应激关键蛋白8-羟基脱氧鸟苷(8-OHdG)、超氧化物歧化酶(SOD)、Bcl-2、葡萄糖调节蛋白78(GRP78)的表达水平。结果与C组相比,DM组大鼠空腹血糖明显升高,毛发干枯,体质量增长缓慢。与C组比较,DM组大鼠SOD、Bcl-2蛋白表达水平明显降低,8-OHdG、GRP78蛋白表达水平明显升高(均P<0.05);而TDM组大鼠SOD、Bcl-2蛋白表达水平明显高于DM组,8-OHdG、GRP78蛋白表达水平明显低于DM组(均P<0.05)。结论曲美他嗪可能通过提高糖尿病大鼠心肌组织中SOD、Bcl-2的表达,抑制氧化应激引起的心肌细胞凋亡,对心肌细胞起保护作用。曲美他嗪降低糖尿病大鼠心肌组织8-OHdG、GRP78的表达,可能影响内质网应激引起的心肌细胞凋亡,降低心肌细胞的损伤。

Objective To establish a diabetic rat model and explore the effect of trimetazidine on the oxidative and endoplasmic reticu-lum stress levels of the myocardial tissue of the diabetic rats.Methods Thirty healthy male SD rats were randomly divided into control,diabetes,and diabetes+trimetazidine treatment groups(groups C,DM,and TDM,respectively).The rats in group C were fed a standard diet;those in groups DM and TDM were fed a high-fat diet and given a single intraperitoneal injection of streptozotocin(30 mg/kg)after feeding for 4 weeks;those in group TDM were given trimetazidine(20 mg·kg^(-1)·d^(-1))for 4 weeks.The expression levels of key proteins,8-hydroxy-2’-deoxyguanosine(8-OHdG),superoxide dismutase(SOD),Bcl-2,and glucose-regulated protein 78(GRP78)were detect-ed.Results Compared with group C,the fasting blood glucose levels in group DM were significantly higher,coupled with a slow body we ight increase.Compared with group C,the SOD and Bcl-2 expression levels significantly decreased and the 8-OHdG and GRP78 expres-sion levels significantly increased in the group DM(all P<0.05).While the SOD and Bcl-2 expression levels in group TDM were signifi-cantly higher,the 8-OHdG and GRP78 expression levels were significantly lower than those in group DM(all P<0.05).Conclusion Tri-metazidine could increase SOD and Bcl-2 expression in the myocardial tissue of diabetic rats,inhibit oxidative stress-induced apoptosis,and protect cardiomyocytes.Trimetazidine reduces the expression of 8-OHdG and GRP78 in the myocardial tissue of diabetic rats,which might affect apoptosis caused by endoplasmic reticulum stress and reduce cardiomyocyte damage.