Hypoxia Up-regulates Expression of Peroxisome Proliferator-activated Receptor γ Angiopoietin-related Gene (PGAR) in Cardiomyocytes: Role of Hypoxia Inducible Factor 1α

A. J. Belanger, H. Lu, T. Date, L. X. Liu, K. A. Vincent, G. Y. Akita, S. H. Cheng, R. J. Gregory and C. Jiang. Hypoxia Up-regulates Expression of Peroxisome Proliferator-activated Receptor γ Angiopoietin-related Gene (PGAR) in Cardiomyocytes: Role of Hypoxia Inducible Factor 1α. Journal of Molecular and Cellular Cardiology (2002)34 , 765–774. Peroxisome proliferator-activated receptors (PPAR), especially the PPARα and PPARγ, are associated with an extraordinary diverse spectrum of cardiovascular diseases including hypertension, angiogenesis, cardiac hypertrophy, and atherosclerosis. PGAR (for PPAR γ angiopoietin-related gene) is a recently identified PPAR target gene which is associated with adipose differentiation, systemic lipid metabolism, energy homeostasis, and possibly angiogenesis. We report here that WY-14643, a selective PPARα ligand up-regulated PGAR expression in neonatal rat cardiomyocytes. In parallel to activating the expression of vascular endothelial growth factor and glucose transporter-4, hypoxia increased PGAR mRNA levels. PGAR expression was also increased by desferrioxamine and CoCl2, but not by sodium cyanide, results consistent with the pharmacological features of hypoxia-responsive genes. These studies are the first to demonstrate that hypoxia increases the mRNA levels of a PPAR target gene in cardiomyocytes. Furthermore, infection with adenoviral vectors encoding the wild-type or a hybrid form of HIF-1α highly increased PGAR mRNA levels. In contrast, neither hypoxia nor overexpression of HIF-1α affected the mRNA levels of PPARα, PPAR γ, and muscle carnitine palmitoyltransferase, a known PPARα target gene. These results suggest that hypoxic activation of PGAR expression is likely mediated by HIF-1 but not the PPARα/RXR pathway.