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 Angiopoietin-related Gene (PGAR) in Cardiomyocytes: Role of Hypoxia Inducible Factor la. Journal of Molecular and Cellular Cardiology (2002) 34, 765-774. Peroxisome proliferator-activated receptors (PPAR), especially the PPARalpha and PPARgamma, are associated with an extraordinary diverse spectrum of cardiovascular diseases including hypertension, angiogenesis, cardiac hypertrophy, and atherosclerosis. PGAR (for PPARgamma 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 PPARalpha 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 wildtype or a hybrid form of HIF-1alpha highly increased PGAR mRNA levels. In contrast, neither hypoxia nor overexpression of HIF-1alpha affected the mRNA levels of PPARalpha, PPARgamma, and muscle carnitine palmitoyltransferase, a known PPARalpha target gene. These results suggest that hypoxic activation of PGAR expression is likely mediated by HIF-1 but not the PPARalpha/RXR pathway. (C) 2002 Elsevier Science Ltd. All rights reserved.