| First Author | Gong K | Year | 2011 |
| Journal | J Hypertens | Volume | 29 |
| Issue | 9 | Pages | 1810-9 |
| PubMed ID | 21836474 | Mgi Jnum | J:281893 |
| Mgi Id | MGI:6367490 | Doi | 10.1097/HJH.0b013e32834a4d03 |
| Citation | Gong K, et al. (2011) Transforming growth factor-beta inhibits myocardial PPARgamma expression in pressure overload-induced cardiac fibrosis and remodeling in mice. J Hypertens 29(9):1810-9 |
| abstractText | OBJECTIVES: Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to attenuate pressure overload-induced cardiac fibrosis, suggesting that PPARgamma 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 PPARgamma 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 PPARgamma 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 (DnTGFbetaRII), in which TGF-beta signaling is blocked. In isolated mouse cardiac fibroblasts, we demonstrated that TGF-beta1 treatment decreased steady state PPARgamma mRNA (-34%) and protein (-52%) levels, as well as PPARgamma transcriptional activity (-53%). Chromatin immunoprecipitation analysis showed that TGF-beta1 treatment increased binding of Smad2/3, Smad4 and histone deacetylase 1, and decreased binding of acetylated histone 3 to the PPARgamma promoter in cardiac fibroblasts. Both pharmacological activation and overexpression of PPARgamma significantly inhibited TGF-beta1-induced extracellular matrix molecule expression in isolated cardiac fibroblasts, whereas treatment with the PPARgamma agonist rosiglitazone inhibited, and treatment with the PPARgamma 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-beta1 directly suppresses PPARgamma expression in cardiac fibroblasts via a transcriptional mechanism and suggest that the down-regulation of endogenous PPARgamma expression by TGF-beta may be involved in pressure overload-induced cardiac fibrosis. |
