α-硫辛酸对糖尿病大鼠内质网应激介导影响

Effect of alpha lipoic acid on myocardial apoptosis mediated by endoplasmic reticulum stress in diabetic rats

目的探讨α-硫辛酸对内质网应激介导的糖尿病大鼠心肌细胞凋亡影响。方法选择SD雄性健康大鼠50只,体重250～300 g,用链脲佐菌素建立糖尿病模型,实验设对照组,糖尿病组,α-硫辛酸低、中、高剂量组(15、30、60 mg/kg灌胃12周),对照组和糖尿病组每日给予等量生理盐水灌胃,测定大鼠血糖、心功能、心脏指数及左心室指数;原位末端转移酶标记技术检测细胞凋亡;western blotting检测葡萄糖调节蛋白78(GRP78)与C/EBP环磷酸腺苷反应元件结合转录因子同源蛋白(CHOP)的蛋白表达。结果与对照组比较,糖尿病组大鼠血糖[(26.15±4.24)mmol/L]和心功能左室舒张末压(LVEDP)[(9.57±1.16)mm Hg]均升高(P<0.05),右心室收缩压(LVSP)[(62.45±4.10)mm Hg]、±dp/dtmax[(4 502.32±238.92)mm Hg/s]均降低(P<0.05);与糖尿病组比较,α-硫辛酸干预组各指标得到改善;与对照组比较,糖尿病组大鼠心肌细胞凋亡率[(11.28±0.33)%]增加(t=3.875,P<0.05),GRP78与CHOP蛋白表达比值升高;与糖尿病组比较,α-硫辛酸组心肌细胞凋亡率降低,GRP78与CHOP蛋白表达降低(P<0.01)。结论α-硫辛酸对糖尿病大鼠心肌有保护作用,其作用机制可能与内质网应激有关。

Objective To explore the effect of alpha lipoic acid（A-LA） on myocardial apoptosis mediated by endo- plasmic reticulum stress （ERS） in diabetic rats. Methods Fifty healthy male Sprague-Dawley rats with 250 to 300 g of body weight were selected. The rat diabetes model was established with streptozotocin（STZ） and the diabetic rats were randomly divided into 5 groups ： normal group, diabetic group, low, moderate, and high dose A-LA groups at the doses of 15,30, and 60 mg/kg/d by gastric gavage for 12 weeks. The normal group and diabetic group were treated with normal saline daily. Blood glucose, cardiac function, cardiac mass index, and left ventricular mass index of the rats were deter- mined. Apoptosis was detected by TdT-mediated dUTP nick end labeling （TUNEL）. The expressions of glucose-regulated protein 78 （GRP78） and C/EBP homologous protein （CHOP） were detected with western blotting. Results Compared to those of the control group, blood sugar （ 26. 15± 4. 24 mmol/L） and left ventricular end-diastolic pressure （LVEDP） （9.57±1.16 mmHg）of the diabetic group were significantly increased（ P 〈 0.01 ）, but left ventricular systolic pressure （LVSP[62.45 ± 4. 10 mmHg] ）, ± maximun rate-of-rise left ventricular pressure （LVdp/dtmax [ 4502. 32 ± 238. 92 mmHg/s ] ）were significantly reduced（ P 〈 0. 01 ）. The indexes of ventricular mass and left vertricular mass were signifi- cantly higher in diabetic rats and the indexes of A-LA treatment groups were improved compared to the diabetic group. Compared to the control group, the apoptosis of diabetic rats （ 11.28 ± 0. 33 % ） increased significantly （P 〈 0. 05） and the expressions of GRP78 and CHOP protein were increased. The apoptosis of A-LA treatment groups was significantly re- duced and GRP78 and CHOP protein expressions were decreased（P 〈 0. 01 ）. Conclusion A-LA has protective effect on cardiomvonathv in diabetic rats and its mechanism may be associated with ERS.