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

Objectives Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to attenuate pressure overload-induced cardiac fibrosis, suggesting that PPARg has an antifibrotic effect. This study tested the hypothesis that there is a functional interaction between transforming growth factor-beta (TGF-beta) signaling and endogenous PPAR gamma 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 PPAR gamma protein levels were decreased in wild-type mice, but increased in mice with an inducible overexpression of dominant negative mutation of the human TGF-beta type II receptor (DnTGF beta RII), in which TGF-beta signaling is blocked. In isolated mouse cardiac fibroblasts, we demonstrated that TGF-beta 1 treatment decreased steady state PPAR gamma mRNA (-34%) and protein (-52%) levels, as well as PPAR gamma transcriptional activity (-53%). Chromatin immunoprecipitation analysis showed that TGF-beta 1 treatment increased binding of Smad2/3, Smad4 and histone deacetylase 1, and decreased binding of acetylated histone 3 to the PPAR gamma promoter in cardiac fibroblasts. Both pharmacological activation and overexpression of PPAR gamma significantly inhibited TGF-beta 1-induced extracellular matrix molecule expression in isolated cardiac fibroblasts, whereas treatment with the PPAR gamma agonist rosiglitazone inhibited, and treatment with the PPAR gamma 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-beta 1 directly suppresses PPAR gamma expression in cardiac fibroblasts via a transcriptional mechanism and suggest that the down-regulation of endogenous PPAR gamma expression by TGF-beta may be involved in pressure overload-induced cardiac fibrosis. J Hypertens 29: 1810- 1819 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.