Abstract 16629: Empagliflozin Directly Stimulates PGC-1α-Dependent Mitochondrial Biogenesis in Cardiac Cells; A Potential Mechanism Associated With Its Cardiovascular Benefits

Empagliflozin (EMP) is a member of the gliflozin class of drugs used to treat type 2 diabetes mellitus (T2DM). These drugs inhibit the sodium glucose co-transporter 2 (SGLT-2) and facilitate glucose disposal via the kidneys. There is considerable interest in the growing evidence that select anti-diabetic drugs such as empagliflozin may have a cardioprotective effect independent of glycemic control manifested as a reduction in the risk of developing a major adverse cardiovascular event (MACE). The mechanism(s) underlying this effect are unknown. To test the hypothesis that the beneficial cardiac effects of EMP may be mediated by enhancing mitochondrial turnover, specifically enhanced mitophagy and mitochondrial biogenesis, we treated 5 day differentiated H9C2 rat ventricular cardiomyocytes with 100nM EMP for 24h. As shown below, we found that EMP increases several markers of mitochondrial mass assessed by western blot. Seahorse respirometry confirmed that this translates to increased basal and maximal respiratory capacity of the cardiomyocyte. Moreover, these findings were associated with increased translocation of PGC-1α to the nucleus suggesting that EMP-mediated mitochondrial biogenesis is PGC-1α-dependent. To determine if increased mitochondrial biogenesis was SGLT-2 receptor mediated we interrogated the protein expression in our differentiated H9C2 cardiomyocytes and in several tissues of the mouse. We detected protein expression in our differentiated H9C2 cardiomyocytes and in mouse heart, liver, adipose, kidney, lung, and spleen. Whether EMP-mediated stimulation of mitochondrial biogenesis is related to SGLT-2 receptor inhibition, or if this process is linked to its ability to improve cardiac function has yet to be determined. Our findings suggest however that a possible mechanism underlying the reduction in MACE associated with EMP treatment may be due in part to its effect on mitochondrial turnover.