Mechanisms responsible for cardioprotective effects of SGLT2 inhibitors: molecular, functional and translational approach

Abstract

Type 2 diabetes mellitus (T2D) is considered one of the main risk factors for cardiovascular diseases (CVD), which are responsible for 80% of the premature mortality of the diabetic population. Among CVD, heart failure is a common complication of T2D, occurring in more than one in 5 patients aged over 65 years. Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors emerged as promising antidiabetic drugs, decreasing glucose reabsorption as well as cardiovascular mortality and the number of hospitalization for heart failure in T2D patients. Moreover, preliminary data from our research group suggest that SGLT2 inhibitors cause beneficial cardiovascular effects independent of glycemic control. However, the cardioprotective mechanisms of these drugs remain unknow. Thus, our aim of this work is to elucidate the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors. Direct and indirect effects of SGLT2 inhibitor empagliflozin over human and animal cardiomyocytes will be evaluated. Human cardiomyocytes derived from induced pluripotent stem cells (CM-iPSCs) and isolated from neonatal rats submitted to hypoxia will be incubated with empagliflozin or serum from rats with heart failure treated or not with this drug. Then, we will execute analysis of ion homeostasis, Ca+2 mobilization and relative expression of cardiac proteins, electrophysiological characterization and evaluation of reactive oxygen species (ROS) production. Finally, metabolomic analysis will be performed to investigate the enzymatic and metabolic pathways that mediate the cardioprotective effects. We hope that these results may contribute to the development of efficient pharmacological therapy, with great potential for better clinical management of millions individuals with heart failure.