title: Transforming growth factor-β inhibits myocardial PPARγ expression in pressure overload-induced cardiac fibrosis and remodeling in mice.
abstract: OBJECTIVE
  Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to attenuate pressure overload-induced cardiac fibrosis, suggesting that PPARγ has an antifibrotic effect. This study tested the hypothesis that there is a functional interaction between transforming growth factor-β (TGF-β) signaling and endogenous PPARγ expression in cardiac fibroblasts and pressure overloaded heart.
  
  
  RESULTS
  We observed that, in response to pressure overload induced by transverse aortic constriction, left-ventricular PPARγ protein levels were decreased in wild-type mice, but increased in mice with an inducible overexpression of dominant negative mutation of the human TGF-β type II receptor (DnTGFβRII), in which TGF-β signaling is blocked. In isolated mouse cardiac fibroblasts, we demonstrated that TGF-β1 treatment decreased steady state PPARγ mRNA (-34%) and protein (-52%) levels, as well as PPARγ transcriptional activity (-53%). Chromatin immunoprecipitation analysis showed that TGF-β1 treatment increased binding of Smad2/3, Smad4 and histone deacetylase 1, and decreased binding of acetylated histone 3 to the PPARγ promoter in cardiac fibroblasts. Both pharmacological activation and overexpression of PPARγ significantly inhibited TGF-β1-induced extracellular matrix molecule expression in isolated cardiac fibroblasts, whereas treatment with the PPARγ agonist rosiglitazone inhibited, and treatment with the PPARγ antagonist T0070907 exacerbated chronic pressure overload-induced cardiac fibrosis and remodeling in wild-type mice in vivo.
  
  
  CONCLUSIONS
  These data provide strong evidence that TGF-β1 directly suppresses PPARγ expression in cardiac fibroblasts via a transcriptional mechanism and suggest that the down-regulation of endogenous PPARγ expression by TGF-β may be involved in pressure overload-induced cardiac fibrosis.
authors.affiliation: Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Kaizheng
authors.initials: K
authors.lastname: Gong
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Jason A
authors.initials: JA
authors.lastname: Lucas
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Hage
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: Dongqi
authors.initials: D
authors.lastname: Xing
mesh_terms: D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011312:Pressure; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D017931:DNA Primers; D047495:PPAR gamma; D016212:Transforming Growth Factor beta