gw-501516 and Fibrosis

The airway wall remodeling observed in asthma is associated with subepithelial fibrosis and enhanced activation of human bronchial fibroblasts (HBFs) in the fibroblast to myofibroblast transition (FMT), induced mainly by transforming growth factor-β (TGF-β). The relationships between asthma severity, obesity, and hyperlipidemia suggest the involvement of peroxisome proliferator-activated receptors (PPARs) in the remodeling of asthmatic bronchi. In this study, we investigated the effect of PPARδ ligands (GW501516 as an agonist, and GSK0660 as an antagonist) on the FMT potential of HBFs derived from asthmatic patients cultured in vitro. This report shows, for the first time, the inhibitory effect of a PPARδ agonist on the number of myofibroblasts and the expression of myofibroblast-related markers-α-smooth muscle actin, collagen 1, tenascin C, and connexin 43-in asthma-related TGF-β-treated HBF populations. We suggest that actin cytoskeleton reorganization and Smad2 transcriptional activity altered by GW501516 lead to the attenuation of the FMT in HBF populations derived from asthmatics. In conclusion, our data demonstrate that a PPARδ agonist stimulates antifibrotic effects in an in vitro model of bronchial subepithelial fibrosis. This suggests its potential role in the development of a possible novel therapeutic approach for the treatment of subepithelial fibrosis during asthma.

Topics: Asthma; Bronchi; Cells, Cultured; Fibroblasts; Fibrosis; Humans; Myofibroblasts; PPAR delta; Transforming Growth Factor beta; Transforming Growth Factor beta1

The development of heart failure is invariably associated with extensive fibrosis. Treatment with Peroxisome Proliferator-Activated Receptor (PPAR) ligands has been shown to attenuate cardiac fibrosis, but the molecular mechanism underlying this protective effect has remained largely unknown. In this study the potential of each PPAR isoform (PPARalpha, delta, and gamma) to attenuate cardiac fibroblast proliferation, fibroblast (CF) to myofibroblast (CMF) transdifferentiation, and collagen synthesis was investigated.. PPARdelta was found to be the most abundant isoform in both CF and CMF. Only the PPARdelta ligand GW501516, but not PPARalpha ligand Wy-14,643 or PPARgamma ligand rosiglitazone, significantly increased PPAR-dependent promoter activity and expression of the PPAR-responsive gene UCP2 ( approximately 5-fold). GW501516 reduced the proliferation rate of CF (-38%) and CMF (-26%), which was associated with increased expression of the cell cycle inhibitor gene G0/G1 switch gene 2 (G0S2). Exposure of CF to the PPARdelta ligand or adenoviral overexpression of PPARdelta significantly decreased alpha-smooth muscle actin (alpha-SMA) levels, indicating a reduced CF to CMF transition. The inhibition of transdifferentiation by PPARdelta correlated with an increase in PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome ten) expression. (3)H-Proline incorporation assays demonstrated a GW501516 induced decline in collagen synthesis (-36%) in CF.. Cardiac fibroblast proliferation, fibroblast to myofibroblast differentiation and collagen synthesis were reduced after activation of PPARdelta, suggesting that PPARdelta represents an attractive molecular target for attenuating cardiac fibrosis.

Topics: Animals; Animals, Newborn; Cell Differentiation; Cell Proliferation; Cells, Cultured; Collagen; Fibroblasts; Fibrosis; Humans; Immunohistochemistry; Ligands; Myocytes, Cardiac; Peroxisome Proliferators; PPAR alpha; PPAR delta; PPAR gamma; Pyrimidines; Rats; Rats, Inbred Lew; Rosiglitazone; Thiazoles; Thiazolidinediones; Transduction, Genetic