Dapagliflozin Improves Diabetic Cardiomyopathy by Modulating the Akt/mTOR Signaling Pathway

Abstract

Background. Dapagliflozin can significantly improve heart failure, and Cx43 is one of the molecular mechanisms of heart failure. This study investigated the effect of dapagliflozin on Cx43 and Akt/mTOR signaling pathway in ventricular myocytes. Methods. A rat model of type 2 diabetes mellitus was established by high-fat diet combined with streptozotocin, and the animals were treated randomly with dapagliflozin. The morphological changes of the myocardium were observed by hematoxylin eosin staining, and the expression and distribution of Cx43 in ventricular myocytes were detected by immunohistochemistry. And Western blot determined the expressions of Cx43, Akt, mTOR, p62, and LC3 proteins in rat myocardium. Results. Compared with the normal control group, the heart rate of diabetic rats decreased significantly ( $p<0.05$ ), QRS wave of ECG widened, and QT interval prolonged ( $p<0.05$ ). Dapagliflozin treatment in diabetic rats resulted in improvements in these ECG indexes ( $p<0.05$ ) with early administration group obtaining greater efficacy than the late administration group ( $p<0.05$ ). In the normal control group, the cardiomyocytes were arranged orderly, and the expression of Cx43 was dense, uniform, and regular, which was higher than that in the intercalated disc. In the diabetic control model group, the cardiomyocytes were enlarged and presented disorderly with detection of Cx43 in the cytoplasm. Early use of dapagliflozin better improved these myocardial tissue lesions. Of note, as diabetic rats exhibited decreased expression of Cx43, Akt, and mTOR ( $p<0.05$ ), increased p62 expression ( $p<0.05$ ), and decreased LC3-II/I ratio ( $p<0.05$ ), administration of dapagliflozin partially reversed the expression of the above proteins ( $p<0.05$ ) with greater improvement in the early administration group compared with the late administration group ( $p<0.05$ ). Conclusions. Dapagliflozin increases the expression of Cx43 in cardiomyocytes of diabetic rats and thereby alleviates heart failure partly through regulating the Akt/mTOR signaling pathway.