173 - To investigate the Physiological/ Pathophysio-logical Function of Glutaredoxin-1 on the Metabolic Cardiovascular Disease

Abstract

To meet the constant energy demand, the heart utilizes fatty acid oxidation as the primary source and glucose, lactate, ketone bodies, and pyruvate as secondary sources to generate ATP. The healthy heart quickly adapts to changes in the abundance of these metabolites. Type II diabetes (T2D), however, impairs this metabolic flexibility, in part to insulin resistance. The loss of metabolic flexibility in T2D can damage cardiomyocytes leading to cardiomyopathy, cardiac remodeling and heart failure. Glutaredoxin-1 (Glrx) is an enzyme that removes glutathione adducts from proteins and participates in redox signaling. Ablation of Glrx perturbs lipid metabolism and causes dyslipidemia and obesity in mice. Glrx knockout mice fed high fat high sucrose (HFHS) diet for six months developed systolic dysfunction which led to around 25% decrease ejection fraction and fractional area shortening. Global gene expression analysis revealed changes in important metabolic enzymes including upregulation of pyruvate dehydrogenase kinase (PDK) 4 in Glrx KO hearts. PDK4 inhibits pyruvate dehydrogenase, which links glucose metabolism with the Krebs cycle and mitochondrial respiration. Upregulation of PDK4 limits glucose catabolism and increases fatty acid oxidation. Furthermore, other biomarkers of fibrosis and cardiac remodeling including CTGF and matrix metalloproteinases inhibitor (Timp3) were changed in HFHS fed Glrx KO mice. Overall, our data suggests that Glrx may play an important role in regulating cardiac lipid metabolism and metabolic flexibility that can lead to metabolic cardiomyopathy.