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

• Published in: Journal of molecular and cellular cardiology 2002-07, Vol.34 (7), p.765-774
• Main Authors: Belanger, Adam J., Lu, Hsienwie, Date, Taro, Liu, Louis X., Vincent, Karen A., Akita, Geoffery Y., Cheng, Seng H., Gregory, Richard J., Jiang, Canwen
• Format: Article
• Language: English
• Subjects: Angiopoietin; Angiopoietin-related proteins; Hypoxia, HIF-1, PPAR, PGAR
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1006/jmcc.2002.2021

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 PPARγ 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, PPARγ, 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.