Abstract 523: Pioglitazone and Glucagon-like Peptide 1 Receptor Agonist Stimulate Mitochondrial Turnover in the Heart When Administered After the Infarct in Obese Mice

Abstract

Randomized clinical trials have demonstrated that pioglitazone (PIO), a thiazolidinedione, and liraglutide and semaglutide, glucagon-like peptide-1 receptor agonists (GLP1Ra), are effective in treating Type 2 diabetes mellitus. Of considerable interest is the additional observation that they may also be effective in reducing the incidence of major adverse cardiovascular events (MACE) independent of glycemic control. The mechanism underlying this protection is unknown. To test the hypothesis that enhanced mitochondrial turnover (mitophagy and mitochondrial biogenesis) might play a role, obese mice with insulin resistance were subjected to permanent coronary artery ligation (PCAL). Two hours later they were administered an i.p. bolus of vehicle (50μL DMSO), PIO (10mg/kg), or a GLP1Ra (10nmoles/25g) (Sigma). This was repeated every other day for 2 weeks. Hearts were probed by western blot for markers of mitochondrial biogenesis and mitophagy. As shown, PIO was a strong inducer of mitochondrial biogenesis evidenced by increased mitochondrial markers in the whole lysate (mitochondrial biogenesis) whereas GLP1Ra stimulated mitophagy, indicated by Parkin, p62 and optineurin translocation to the mitochondrial fraction. These findings suggest that enhanced mitochondrial biogenesis and mitophagy may be important therapeutic targets for the prevention of adverse cardiovascular outcomes. If confirmed, enhanced mitochondrial turnover may be one of the mechanisms underlying the reduced incidence of MACE that was observed in the PROactive (PIO) and the LEADER and SUSTAIN-6 (GLP1Ra) clinical trials.