ATORVASTATIN CONFERS MYOCARDIAL PROTECTION ON RATS WITH DIABETIC CARDIOMYOPATHY BY INHIBITING THE ATF6/CHOP/PUMA SIGNALLING PATHWAY

Wenting Zhang¹, Fei Xue², Jiwei Guo¹, Bin Xu¹, Shuo Geng¹, Ping Du^{1, *}

¹Department of The Third Ward of Cardiology, the First Hospital of Harbin, Harbin 150010, PR China - ²Department of Emergency, Harbin Red Cross Central Hospital, Harbin 150076, PR China

Objective: To analyse the protective effect of atorvastatin on rats with diabetic cardiomyopathy due to inhibition of the ATF6/CHOP/PUMA signalling pathway. 

Methods: Forty-five healthy, clean-grade male Sprague-Dawley rats were fed adaptively for one week. The diabetic cardiomyopathy rat model was then established. A drug group was given atorvastatin at 5 mg/kg/d, while a control group and a model group were given the same amount of saline. Cardiac function (left ventricular diastolic diameter [LVEDD], left ventricular systolic diameter [LVESD] and left ventricular ejection fraction [LVEF]), blood lipid index (serum cholesterol [TC], triglycerides [TG], low-density lipoprotein [LDL] and high-density lipoprotein [HDL]), myocardial tissue changes, and myocardial cell death were measured. Mortality and ATF6, CHOP, PUMA and GRP78 protein expression in the myocardium. 

Results: Compared to the control group, the model and drug groups had significantly higher FBG, and the model group had significantly reduced weight (p<0.05). Compared to the model group, the weight of the drug group was significantly higher weight (p<0.05). The FBG of the drug group was lower than that of the model group, but this difference was not significant (p>0.05). LDL, TG, TC, LVEDD and LVESD levels in the model group and the drug group were significantly higher than those in the control group, while HDL and LVEF levels were significantly lower (p<0.05). Compared to the model group, LDL, TG, TC, LVEDD and LVESD levels in the drug group were significantly lower, and HDL and LVEF levels were significantly higher (p<0.05). In the control group, cardiac myocytes were normal, with clear structure and nuclei of generally similar shape and size; in the model group, cardiac myocytes were disordered, mast cells were present, and the shape and size of nuclei were different; in the drug group, cardiac myocytes were clearly improved compared to those of the model group. The apoptotic cells were labelled yellowish-brown in the TUNEL assay. The apoptosis rate of cardiomyocytes in the model group was significantly lower than that in the control group. After atorvastatin intervention, the apoptosis rate of cardiomyocytes was significantly improved. Compared to the control group, ATF6, CHOP, PUMA and GRP78 expression in the myocardium of the model and drug groups was significantly higher, while the expression of these proteins in the drug group was significantly lower than that of the model group (p<0.05). 

Conclusion: Atorvastatin can inhibit ATF6/CHOP/PUMA signalling pathway activation, reduce myocardial cell apoptosis and fibrosis, and improve cardiac function in rats with diabetic cardiomyopathy.