Class Effect of SGLT2 Inhibitors Against Doxorubicin-Induced Cardiotoxicity via Regulating Adenosine Kinase Mediated-Cardiac Oxidative Stress.

Abstract

PURPOSE: Doxorubicin-induced cardiotoxicity (DIC) limits its clinical application. While individual SGLT2 inhibitors have shown cardioprotective effects, it remains unclear whether this is a class effect and whether the underlying mechanisms are shared. METHODS: A mouse model of DIC was established through the administration of six weekly intraperitoneal injections of doxorubicin at a dose of 2.5 mg/kg. To compare the protective effects, three different SGLT2 inhibitors were administered orally. Cardiac function, cardiac fibrosis, and markers of oxidative stress were assessed. Target prediction, cardiac adenosine ELISA assays, cardiac expression of adenosine kinase (ADK) and ADK siRNA and plasmid were conducted to identify potential targets of SGLT2 inhibitors. In another cohort, DIC mice were treated with the selective ADK inhibitor ABT-702, and cardiac function, fibrosis, and oxidative stress markers were similarly assessed. RESULTS: All three SGLT2 inhibitors provided similar protection against doxorubicin-induced cardiotoxicity, improved ejection fraction (EF%), reduced left ventricular internal diameter in diastole (LVIDd), and attenuated cardiac fibrosis and oxidative stress. ADK was identified as the potential target. SGLT2 inhibitors reduced the overexpression of ADK in DIC and restored adenosine levels in heart tissues. Knockdown and overexpression of ADK revealed that SGLT2i regulated cellular oxidative stress in an ADK-dependent manner. Additionally, ABT-702 similarly protected against doxorubicin-induced cardiotoxicity by modulating oxidative stress in vivo. CONCLUSION: These findings support a class effect of SGLT2 inhibitors in protecting against DIC, likely via inhibition of ADK-mediated oxidative stress. ADK may represent a promising therapeutic target for DIC management.