title: Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1alpha.
abstract: 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 PPAR gamma 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 CoCl(2), 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-1alpha highly increased PGAR mRNA levels. In contrast, neither hypoxia nor overexpression of HIF-1alpha affected the mRNA levels of PPARalpha, PPAR gamma, 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.
authors.affiliation: Genzyme Corporation, 31 New York Avenue, Framingham, MA, 01701, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Belanger
authors.forename: Hsienwie
authors.initials: H
authors.lastname: Lu
authors.forename: Taro
authors.initials: T
authors.lastname: Date
authors.forename: Louis X
authors.initials: LX
authors.lastname: Liu
authors.forename: Karen A
authors.initials: KA
authors.lastname: Vincent
authors.forename: Geoffery Y
authors.initials: GY
authors.lastname: Akita
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gregory
authors.forename: Canwen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D001798:Blood Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: C485792:ANGPTL2 protein, human; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C467629:Angpt1 protein, rat; D001798:Blood Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors