title: Hypoxia induces downregulation of PPAR-γ in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-β signaling.
abstract: Chronic hypoxia activates transforming growth factor-β (TGF-β) signaling and leads to pulmonary vascular remodeling. Pharmacological activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) has been shown to prevent hypoxia-induced pulmonary hypertension and vascular remodeling in rodent models, suggesting a vasoprotective effect of PPAR-γ under chronic hypoxic stress. This study tested the hypothesis that there is a functional interaction between TGF-β/Smad signaling pathway and PPAR-γ in isolated pulmonary artery small muscle cells (PASMCs) under hypoxic stress. We observed that chronic hypoxia led to a dramatic decrease of PPAR-γ protein expression in whole lung homogenates (rat and mouse) and hypertrophied pulmonary arteries and isolated PASMCs. Using a transgenic model of mouse with inducible overexpression of a dominant-negative mutant of TGF-β receptor type II, we demonstrated that disruption of TGF-β pathway significantly attenuated chronic hypoxia-induced downregulation of PPAR-γ in lung. Similarly, in isolated rat PASMCs, antagonism of TGF-β signaling with either a neutralizing antibody to TGF-β or the selective TGF-β receptor type I inhibitor SB431542 effectively attenuated hypoxia-induced PPAR-γ downregulation. Furthermore, we have demonstrated that TGF-β1 treatment suppressed PPAR-γ expression in PASMCs under normoxia condition. Chromatin immunoprecipitation analysis showed that TGF-β1 treatment significantly increased binding of Smad2/3, Smad4, and the transcriptional corepressor histone deacetylase 1 to the PPAR-γ promoter in PASMCs. Conversely, treatment with the PPAR-γ agonist rosiglitazone attenuated TGF-β1-induced extracellular matrix molecule expression and growth factor in PASMCs. These data provide strong evidence that activation of TGF-β/Smad signaling, via transcriptional suppression of PPAR-γ expression, mediates chronic hypoxia-induced downregulation of PPAR-γ expression in lung.
authors.affiliation: Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, 35294, USA.
authors.forename: Kaizheng
authors.initials: K
authors.lastname: Gong
authors.forename: Dongqi
authors.initials: D
authors.lastname: Xing
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Baran
authors.initials: B
authors.lastname: Aksut
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Susan E
authors.initials: SE
authors.lastname: Nozell
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D047495:PPAR gamma; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625843:Tgfbr1 protein, rat; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1