Activation of peroxisome proliferator-activated receptor-γ inhibits transforming growth factor-β1 induction of connective tissue growth factor and extracellular matrix in hypertrophic scar fibroblasts in vitro

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been recently reported to have beneficial effects on organ fibrosis. However, their effects on extracellular matrix (ECM) turnover in hypertrophic scar fibroblasts (HSFs), and the related molecular mechanisms are unknown. HSFs were cultured and exposed to different concentration PPAR-gamma ligands in the presence of transforming growth factor-beta1 (TGF-beta1). In growth-arrested HSFs, a PPAR-gamma natural ligand (15-deoxy-D12,14-prostaglandin J2, 15d-PGJ2) and a synthetic ligand (GW7845) dose-dependently attenuated TGFbeta1-induced expression of Connective tissue growth factor (CTGF), collagens and fibronectin. Furthermore, the suppression of CTGF mRNA and protein expression are relieved by pretreatment with an antagonist of PPAR-gamma (GW9662). Moreover, GW7845 and 15d-PGJ2 partially inhibited the expression and phosphorylation of the TGF-beta1/Smad pathway. These results suggest that in TGFbeta1-stimulated HSFs, PPAR-gamma ligands caused an antiproliferative effect and reduced ECM production through mechanisms that included reducing CTGF expression, and a crosstalk between PPAR-gamma and Smad may be involved in the inhibitory effects of PPAR-gamma ligands.

Novel PPARγ Modulator GED-0507-34 Levo Ameliorates Inflammation-driven Intestinal Fibrosis

“…The main reasons to assess the efficacy of new synthetic PPARγ modulators in the treatment of intestinal fibrosis are due to the evidences that: (i) together with the adipose tissue, the intestine represents the main site where PPARγ achieves the higher tissue expression levels and (ii) PPARγ activation downregulates TGFβ/Smad pathway [7,13,24,25,35,36] .…”

Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications

“…Indeed, several studies have examined the relationship between inhibition of CTGF and reduction of hypertrophic scars. PPARg activators 15d-PGJ2 and GW7845 were found to attenuate TGF-b1-induced expression of CTGF and collagens at both mRNA and protein levels in hypertrophic scar fibroblasts [34]. These data supported the application of PPARg agonists for treatment of hypertrophic scars through modulating CTGF.…”

“…Peroxisome proliferator-activated receptor-g (PPARg) ligands15d-PGJ2 and GW7845 inhibited the expression and phosphorylation of TGF-b1/Smads leading to anti-proliferative effect and reduced ECM production in hypertrophic scar fibroblasts [34]. Recently, many natural compounds have increasingly been demonstrated to have anti-hypertrophic scar properties by interrupting TGF-b1 signaling, including botulinum toxin type A [35], tetrandrine [36], baicalein [16], loureirin B [37,38], and the uighur medicine ASMq [39].…”

Current progress in understanding the molecular pathogenesis of burn scar contracture

“…It has been reported that peroxisome proliferator-activated receptor-γ (PPARγ) ligands, 15d-PGJ2 and GW7845, could inhibit the expression and phosphorylation of TGF-β1/Smads [18]. Either disruption or neutralization of TGF-β/Smads signaling by botulinum toxin type A, tetrandrine, baicalein, loureirin B, or the Uighur medicine ASMq can decrease the myofibroblast properties [19].…”