Dapagliflozin Inhibits Ventricular Remodeling in Heart Failure Rats by Activating Autophagy through AMPK/mTOR Pathway

Abstract

Objective. Heart failure (HF) is the end stage of heart disease caused by various factors which mainly involves ventricular remodeling (VR). In HF patients with reduced ejection fraction, dapagliflozin (DAPA) reduced the risk of worsening HF or cardiovascular death. Thus, we attempted to clarify the specific role of DAPA underlying HF progression. Methods. The HF rat model was established to mimic characteristics of HF in vivo. HE staining assessed histopathological changes in left ventricular myocardial tissue of rats in each group. ELISA measured plasma ANP and BNP levels of rats in each group. M-mode echocardiography detected cardiac function of rats in each group. TUNEL staining detected apoptosis of infarct margin cells in myocardial tissue of rats in each group. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in myocardial tissue of rats in each group. Immunohistochemical staining detected caspase-3 or LC3B level in myocardial tissue of rats in each group. The HF cellular model was established to mimic characteristics of HF in vitro. Flow cytometry detected H9C2 cell apoptosis under different conditions. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in H9C2 cells under different conditions. Immunofluorescence detected caspase-3 or LC3B level in H9C2 cells under different conditions. Results. DAPA attenuated left VR and improved cardiac function in HF rats. DAPA attenuated cardiomyocyte apoptosis in HF rats. DAPA facilitated cardiomyocyte autophagy in HF rats via the AMPK/mTOR pathway. DAPA repressed hypoxia-induced H9C2 cell apoptosis by facilitating autophagy. DAPA repressed hypoxia-induced H9C2 cell apoptosis via the AMPK/mTOR pathway. Conclusion. DAPA suppresses ventricular remodeling in HF through activating autophagy via AMPK/mTOR pathway, which provides a potential novel insight for seeking therapeutic plans of HF.

Dapagliflozin alleviates high glucose‐induced injury of endothelial cells via inducing autophagy

“…In contrast, other studies have provided evidence that autophagy was upregulated in the heart of type 2 diabetic mice 34 . Previous studies have shown that DAPA activates autophagy in cardiomyocytes 35,36 . Although previous studies demonstrated that DAPA activated autophagy, there are no studies on the role of DAPA in HG‐induced autophagy.…”

“…37 Previous studies have shown that DAPA promoted autophagy in the kidney through AMPK/mTOR signalling pathway. 35 Yang et al 38 indicated that DAPA reduced podocyte injury through the mTOR pathway. Activation of AMPK/mTORmediated autophagy by DAPA also reduced collagen deposition and reduced myocardial fibrosis.…”

“…34 Previous studies have shown that DAPA activates autophagy in cardiomyocytes. 35,36 Although previous studies demonstrated that DAPA activated autophagy, there are no studies on the role of DAPA in HGinduced autophagy. We found that DAPA activated autophagy in HUVECs induced by HG.…”

“…mTOR is one of the core molecules of autophagy, and AKT is located upstream of mTOR 37 . Previous studies have shown that DAPA promoted autophagy in the kidney through AMPK/mTOR signalling pathway 35 . Yang et al 38 indicated that DAPA reduced podocyte injury through the mTOR pathway.…”

Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review)

“…Likewise, DAPA represses cardiac remodeling and hypoxia-induced apoptosis in heart failure through the activation of autophagy via the AMPK/mTOR pathway ( 89 ). It also protects against myocardial I/R injury by limiting NLR family pyrin domain containing 3 (NLRP3) inflammatory vesicle activation and regulating autophagy ( 90 ).…”