Journal of Hypertension

Skip Navigation LinksHome > September 2011 - Volume 29 - Issue 9 > Transforming growth factor-β inhibits myocardial PPARγ expre...
Journal of Hypertension:
doi: 10.1097/HJH.0b013e32834a4d03
Original papers: Heart

Transforming growth factor-β inhibits myocardial PPARγ expression in pressure overload-induced cardiac fibrosis and remodeling in mice

Gong, Kaizhenga,d; Chen, Yiu-Faia; Li, Penga; Lucas, Jason A.a; Hage, Fadi G.a; Yang, Qinglinb; Nozell, Susan E.c; Oparil, Suzannea; Xing, Dongqia

Supplemental Author Material
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Objectives: 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.

Methods and 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.

Conclusion: 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.

© 2011 Lippincott Williams & Wilkins, Inc.


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