Empagliflozins effect on molecular processes in hyperglycemia and failing cardiac myocytes
Abstract
In this dissertation I focus on a sodium glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin (EMPA), which is used to treat type 2 diabetes mellitus (T2DM) and more recently heart failure (HF). In clinical trials SGLT2 inhibitors improved cardiovascular outcomes in HF patients regardless of their diabetes status. Preclinical studies demonstrated EMPA’s effects also in ex vivo perfused hearts and isolated cardiomyocytes. However, cardiomyocytes do not express SGLT2, thus the mechanism of EMPA’s direct effects in cardiac myocytes is unknown. EMPA has been shown to inhibit the late sodium current (INaL) in a transverse aortic constriction (TAC) model of HF with reduced ejection fraction (HFrEF). Cardiomyocytes from a murine model of HF with preserved ejection fraction (HFpEF) also exhibited enhancement of the INaL, and importantly, was reversed with EMPA pre-treatment (~4hr), but interestingly this was not observed with acute (~3min) treatment. The same effects were also seen when a calcium/calmodulin dependent protein kinase II (CaMKII) inhibitor and reactive oxygen species (ROS) inhibitor was used. These findings point towards EMPA affecting upstream regulators of the INaL. CaMKII is an important upstream regulator of the INaL and it has increased activity in disease states such as HF. CaMKII can enhance ROS production via NADPH oxidase 2 (NOX2) and increased levels of ROS can oxidize an already active CaMKII to further enhance its activity. Moreover, a shift in cardiac…
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