Transforming growth factor-β inhibits myocardial PPARγ expression in pressure overload-induced cardiac fibrosis and remodeling in mice
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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Kaizheng Gong1, Yiu-Fai Chen, Peng Li
1Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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.
Insights
Transforming growth factor-beta (TGF-β) directly suppresses peroxisome proliferator-activated receptor gamma (PPARγ) expression in cardiac fibroblasts. This suppression contributes to pressure overload-induced cardiac fibrosis, highlighting a key mechanism in heart disease progression.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Fibrosis
- Receptor Signaling Pathways
Background:
- Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPARγ) shows antifibrotic effects in pressure overload models.
- Understanding the interplay between transforming growth factor-beta (TGF-β) and PPARγ is crucial for developing novel therapeutic strategies for cardiac fibrosis.
Purpose of the Study:
- To investigate the functional interaction between TGF-β signaling and endogenous PPARγ expression in cardiac fibroblasts.
- To elucidate the role of PPARγ in pressure overload-induced cardiac fibrosis.
Main Methods:
- Assessed changes in PPARγ protein and mRNA levels in wild-type and genetically modified mice subjected to pressure overload.
- Utilized isolated mouse cardiac fibroblasts to study the effects of TGF-β1 on PPARγ expression and activity.
- Performed chromatin immunoprecipitation assays to analyze the transcriptional regulation of PPARγ by TGF-β1.
- Evaluated the impact of PPARγ activation and antagonism on TGF-β1-induced extracellular matrix expression and in vivo cardiac remodeling.
Main Results:
- Pressure overload decreased cardiac PPARγ levels in wild-type mice, while blocking TGF-β signaling increased them.
- TGF-β1 treatment significantly reduced PPARγ mRNA, protein levels, and transcriptional activity in cardiac fibroblasts.
- TGF-β1 upregulated the binding of Smad2/3, Smad4, and histone deacetylase 1 to the PPARγ promoter, while decreasing acetylated histone 3 binding.
- PPARγ activation inhibited TGF-β1-induced extracellular matrix production, whereas PPARγ antagonism worsened pressure overload-induced cardiac fibrosis and remodeling.
Conclusions:
- TGF-β1 directly suppresses PPARγ expression transcriptionally in cardiac fibroblasts.
- Down-regulation of endogenous PPARγ by TGF-β is implicated in the pathogenesis of pressure overload-induced cardiac fibrosis.
- Targeting the TGF-β-PPARγ axis may offer a therapeutic approach for mitigating cardiac fibrosis.
