title: Time-dependent PPARγ Modulation of HIF-1α Signaling in Hypoxic Pulmonary Artery Smooth Muscle Cells.
abstract: Pathogenesis of pulmonary hypertension is complex and involves activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that shifts cellular metabolism from aerobic respiration to glycolysis, in part, by increasing the expression of its downstream target pyruvate dehydrogenase kinase-1 (PDK-1), thereby promoting a proliferative, apoptosis-resistant phenotype in pulmonary vascular cells. Activation of the nuclear hormone transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), attenuates pulmonary hypertension and pulmonary artery smooth muscle cell (PASMC) proliferation. In the current study, we determined whether PPARγ inhibits HIF-1α and PDK-1 expression in human PASMCs.
  
  
  
  HPASMCs were exposed to normoxia (21% O2) or hypoxia (1% O2) for 2-72 hours ± treatment with the PPARγ-ligand, rosiglitazone (RSG, 10μM).
  
  
  
  Compared to normoxia, HIF-1α mRNA levels were elevated in HPASMC at 2 hours hypoxia and reduced to baseline levels by 24-72 hours. HIF-1α protein levels increased following 4 and 8 hours of hypoxia and returned to baseline levels by 24 and 72 hours. PDK-1 protein levels increased following 24 hours hypoxia and remained elevated by 72 hours. RSG treatment at the onset of hypoxia attenuated HIF-1α protein and PDK-1 mRNA and protein levels at 4, 8 and 24 hours of hypoxia, respectively. However, RSG treatment during final 24 hours of 72-hour hypoxia, an intervention that inhibits HPASMC proliferation, failed to prevent hypoxia-induced PDK-1 expression.
  
  
  
  Hypoxia causes transient activation of HPASMC HIF-1α that is attenuated by RSG treatment initiated at hypoxia onset. These findings provide novel evidence that PPARγ modulates fundamental and acute cellular responses to hypoxia through both HIF-1-dependent and HIF-1-independent mechanisms.
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Justine I
authors.initials: JI
authors.lastname: Blum
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia; Emory Division of Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, Decatur, Georgia.
authors.forename: Kaiser M
authors.initials: KM
authors.lastname: Bijli
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia; Emory Division of Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, Decatur, Georgia.
authors.forename: Tamara C
authors.initials: TC
authors.lastname: Murphy
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia; Emory Division of Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, Decatur, Georgia.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kleinhenz
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia; Emory Division of Pulmonary, Allergy and Critical Care Medicine, Atlanta VA Medical Center, Decatur, Georgia. Electronic address: Michael.hart3@va.gov.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Hart
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000503:physiopathology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D047495:PPAR gamma; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D017346:Protein Serine-Threonine Kinases
keywords: HIF-1α; PDK-1; PPARγ; Pulmonary hypertension; Vascular smooth muscle cell