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

Abstract

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.

Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice

“…Meanwhile, previous studies also demonstrated the TGFβ pathway crosstalks with PPARγ in such a way that TGFβ downregulates PPARγ expression and its downstream effectors 30–32 , while PPARγ ligands counteracted TGFβ-mediated fibrosis 33 ; however, the crosstalk between TGFβ-Smad2 pathway and PPARγ remain unclear in CMs. Our results showed that overexpression of Smad2 decreased the expression of PPARγ in CMs.…”

PPARs: Protectors or Opponents of Myocardial Function?

“…Mice have decreased PPAR γ expression after TAC, which is reversed in mice when TGF β signaling is blocked [ 185 ]. Treatment of mice with rosiglitazone from 3 days before till 3 weeks after TAC decreased fibrosis and hypertrophy, whereas treatment with PPAR γ antagonist had the opposite effect [ 185 ].…”

“…Mice have decreased PPAR γ expression after TAC, which is reversed in mice when TGF β signaling is blocked [ 185 ]. Treatment of mice with rosiglitazone from 3 days before till 3 weeks after TAC decreased fibrosis and hypertrophy, whereas treatment with PPAR γ antagonist had the opposite effect [ 185 ]. In rats with L-NAME induced hypertension, treatment with L-carnitine normalizes hypertension, hypertrophy, fibrosis, PPAR γ expression, and expression of fibrotic factors [ 186 ].…”

Effect of Salusin-ß on Peroxisome Proliferator-Activated Receptor Gamma Gene Expression in Vascular Smooth Muscle Cells and its Possible Mechanism

“…siRNA-mediated inhibition of HDAC3 attenuated angiotensin II mediated reductions in PPARγ abundance in VSMCs [26]. TGF-β1 down-regulates PPARγ gene expression through recruitment of HDAC1 at the PPARγ promoter in cardiac fibroblasts [36]. Importantly, it has been reported that cytoplasmic IκBα increases NF-κB-independent transcription through binding to HDAC1 and HDAC3 [37].…”