| Objectives Observe the effect of telmisartan on the expression of PERK-ATF4-CHOP signaling pathway in rat with type 2 diabetic myocardium damage,study on the protective effect and its possible mechanism of telmisartan on myocardial damage in type 2 diabetes rat,to provide a new target for the prevention and treatment on diabetic myocardial damage.Methods 50 cleaning male Wistar rats were randomly divided into control group(n=10)and experimental group(n=40).The experimental group was fed with high fat feed for one months and type 2 diabetes rat models were induced by intraperitoneal injection of lowdose streptozotocin(25mg/kg).The control group was given ordinary feed,and the same dose of sodium citrate buffer was injected intraperitoneally according to body weight.The fasting blood glucose was monitored three times on the second,third and 14 th day respectively(Glucose,GLU)≥ 16.7 mmol/L,accompanied by increased drinking water,food intake,urine output and body thinness,ie “three more and one less” typical symptoms of diabetes,namely the establishment of a diabetic DM rat model.Diabetes model rats were then randomly divided into diabetes mellitus group,diabetes mellitus + low dose telmisartan group(DM+LT group),diabetes mellitus + middle dose telmisartan group(DM+MT group),diabetes mellitus + high dose telmisartan group(DM+HT group).The control group was treated with citric acid buffer 1ml/d every day for 10 weeks.After intervention,left ventricular intubation was used to measure left ventricular diastolic and systolic function;hematoxylin eosin staining was used to observe the pathological changes of myocardium in each group;myocardial fibrosis in each group was observed by Masson staining;the expression of GRP78 protein was detected by immunohistochemistry;the quantitative expression of GRP78,PERK,ATF4 and CHOP protein was detected by Western blot;Tunel method was used to detect apoptosis in each group.Results 1 Compared with the control group,the blood glucose level of the model group was significantly increased,the body weight was and the heart volume ratio reduced,and the heart volume ratio increased significantly(P<0.05);compared with DMD group,the blood glucose level in DMD+LT group was not significantly different(P>0.05);compared with DMD group,the blood glucose level in DMD+MT and DMD+HT group was significantly lower(P<0.05);compared with the model group,the heart volume ratio of telmisartan treatment group was significantly decreased(P<0.05),there was no significant difference in blood glucose level in low-dose telmisartan group(P>0.05),while the blood glucose level was notably reduced in DMD+MT and DMD+HT group(P<0.05).2 Compared with the control group,the left ventricular diastolic and systolic function was decreased in the model group(P<0.05).Compared with the model group,the heart function of the rats was significantly improved with a statistical difference(P<0.05)in the telmisartan treatment group.3 Compared with the control group,the pathological damage of the myocardial tissuewas obvious in the model group.The myocardial cells were arranged disorderly and loosely,and the myocardial fiber was broken and necrotic.Collagen deposition and severe fibrosis can occur.While in the treatment of telmisartan,the mentioned myocardial pathological lesions above were reduced to varying degrees,and high-dose group had the most obvious effect.4 Compared with the control group,the content of GRP78 in the myocardial tissue of the model group increased with statistical significance(P<0.05),suggesting that endoplasmic reticulum stress appeared in the myocardial tissue of diabetic rats.After treated with different doses of Telmisartan,the content of GRP78 in myocardial tissue decreased,and the difference between the intervention groups was statistically significant(P<0.05).5 Compared with the control group,the expression of GRP78,PERK,ATF4 and CHOPwas significantly increased in the model group(P<0.05).The expression of these indicators could be down-regulated by different doses of telmisartan(P<0.05).And the degree of down-regulation showed a positive correlation with dose.6 Compared with the control group,the number of cardiomyocyte apoptosis increased significantly in the model group(P<0.05).And the number could be reduced by different doses of telmisartan(P<0.05),and the degree of decline was most obvious in the high-dose treatment group.Conclusions 1 Endoplasmic reticulum stress is involved in the occurrence of myocardial injury in diabetes;2 The PERK-ATF 4-CHOP signaling pathway in diabetic myocardium was activated and it induces apoptosis;3 Telmisartan can inhibit the expression of PERKATF 4-CHOP signaling pathway and inhibit the apoptosis of ERS and its mediate cardiac myocytes,and the effect of intervention is dose-dependent. |
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