Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1alpha.
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.
Belanger
Adam J
AJ
Genzyme Corporation, 31 New York Avenue, Framingham, MA, 01701, USA.
Lu
Hsienwie
H
Date
Taro
T
Liu
Louis X
LX
Vincent
Karen A
KA
Akita
Geoffery Y
GY
Cheng
Seng H
SH
Gregory
Richard J
RJ
Jiang
Canwen
C
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
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