Hypoxia induces downregulation of PPAR-γ in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-β signaling.

Academic Article

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.
  • Keywords

  • Animals, Cell Hypoxia, Cell Movement, Cells, Cultured, Down-Regulation, Extracellular Matrix, Histone Deacetylase 1, Hypoxia, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, PPAR gamma, Protein-Serine-Threonine Kinases, Pulmonary Artery, Rats, Rats, Sprague-Dawley, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad Proteins, Transcription, Genetic, Transforming Growth Factor beta
  • Digital Object Identifier (doi)

    Author List

  • Gong K; Xing D; Li P; Aksut B; Ambalavanan N; Yang Q; Nozell SE; Oparil S; Chen Y-F
  • Start Page

  • L899
  • End Page

  • L907
  • Volume

  • 301
  • Issue

  • 6