Alteration of PGC1-α in the Mitochondrial Homeostasis of Cardiomyocytes under Hyperglycemia. Role of the GLP-1R Activation

Introduction: Cardiovascular disease is the major cause of morbidity and mortality in diabetic patients, and mitochondrial homeostasis can be a key organelle in cardiomyocytes. Peroxisome proliferator-activated receptor- gamma coactivator-alpha (PGC-1α), a master transcription factor of mitochondrial function, may be regulated under hyperglycemic stimulus and anti-diabetic drugs, such as Glucagon-like protein-1 receptor agonists (GLP-1RA). Methodology: The mitochondrial protein expression of PGC-1α and Cytochrome-C was evaluated under 25 mM glucose (HG) and/or GLP-1RA stimulation in H9c2 cardiomyocytes after 18-48 hours. Western blotting was performed from cytosolic and enriched mitochondrial fractions. Also, PGC-1α related genes (Cpt1a, Sdhb, Mfn1 and Nrf1) were quantified by qPCR assay. Results: Mitochondrial PGC-1α and Cytochrome-C, but not TFAM and PPARd, were increased only after 24h of HG. However, at this time, the levels of Cpt1a, Sdhb, Mfn1 and Nrf1 were differentially regulated. Interestingly, co- incubation with GLP-1 and GLP-1RA attenuated expression of both PGC-1 and Cytochrome-C at the mitochondrial location. Conclusions: Hyperglycemia may damage the myocardium by increase of cellular oxidation, but it also could enhance early-responses of cardioprotection by enhancing PGC-1α and Cytochrome-C at the mitochondria. Interestingly, activation of GLP-1RA may attenuate this effect, suggesting a new mechanism of action for GLP-1RA drugs.