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 Left ventricular (LV) remodeling and dysfunction in DOX-treated rats were alleviated with EMPA. BNP, cTnT, and BP were reduced by EMPA. Cardiomyocyte hypertrophy, fibrosis, apoptosis, and LV conduction were improved by EMPA and Los, while Los was inferior to that of EMPA. DOX suppressed L-type calcium current (I Ca,L ) and prolonged action potential duration (APD) both in rats and NRVCMs. EMPA increased I Ca,L , 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.