Empagliflozin protects against doxorubicin-induced arrhythmia by AMPK/mTOR-mediated autophagy in cardiomyocyte

AIM: This study aims to investigate the efficacy of SGLT2i in mitigating DOX-associated ventricular arrhythmias and explore the underlying molecular mechanisms. METHODS: Rats received DOX(5 mg/kg/week i.p., 4 weeks) to model cardiotoxicity; saline-injected rats served as controls. DOX-treated rats were orally administered empagliflozin(EMPA, 10 mg/kg/day) or losartan (Los, 20 mg/kg/day). Cardiac structure and function were assessed. Then left ventricles were prepared for histology, the whole-cell patch clamp, and Western blot measurements. The direct impact of EMPA on neonatal rat ventricular cardiomyocytes (NRVCMs) were also investigated. RESULTS: , shorted APD, and reduced levels of Cav1.2, BNP, and fibrosis proteins(COL1A1, COL3A1, MMP-2, MMP-9). Activation of AMPK and inactivation of mTOR were induced by EMPA in DOX-treated rats and NRVCMs. These effects of EMPA were attenuated when treatment with compound C, an AMPK inhibitor. EMPA restored autophagic flux in DOX-treated rats and NRVCMs in an AMPK-dependent manner. The cardio-protective effects of EMPA were attenuated when treatment with 3-MA, an autophagy inhibitor. CONCLUSION: Our research demonstrated for the first time that EMPA reduced the incidence of ventricular arrhythmia by regulating AMPK/mTOR signaling and restored autophagic flux in DOX-treated rats and NRVCMs.