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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

doi: 10.1097/HJH.0b013e32834a4d03
Original papers: Heart

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.

aVascular Biology and Hypertension Program, Department of Medicine

bDepartment of Nutrition Sciences

cDepartment of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA

dDepartment of Cardiology, The Second Clinical Medical School, Yangzhou University, Yangzhou, China

Correspondence to Suzanne Oparil, MD, 703 19TH ST S, Birmingham, AL 35294, USATel: +1 205 934 2580; fax: +1 205 934 0424; e-mail: soparil@uab.edu

Abbreviations: α-SMA, α-smooth muscle actin; AcH3, acetylated histone3; CFs, cardiac fibroblasts; ChIP, chromatin immunoprecipitation; CTGF, connective tissue growth factor; DnTGFβRII, dominant negative TGF-β receptor type II; ECM, extracellular matrix; FBS, fetal bovine serum; HDAC1, histone deacetylase 1; LV, left ventricle; LVEDP, left ventricular end-diastolic pressure; PPARγ, peroxisome proliferator-activated receptor gamma; TAC, transverse aortic constriction; TGF-β, transforming growth factor-β

Received 26 January, 2011

Revised 9 June, 2011

Accepted 27 June, 2011

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© 2011 Lippincott Williams & Wilkins, Inc.