Activation of PPARδ inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts

Objective: 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 (PPAR alpha, delta, and gamma) to attenuate cardiac fibroblast proliferation, fibroblast (CF) to myofibroblast (CMF) transdifferentiation, and collagen synthesis was investigated. Methods and results: PPAR8 was found to be the most abundant isoform in both CF and CMF. Only the PPAR delta ligand GW501516, but not PPAR(x ligand Wy-14,643 or PPAR-gamma ligand rosiglitazone, significantly increased PPAR-dependent promoter activity and expression of the PPAR-responsive gene UCP2 (similar to 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 PPAR8 ligand or adenoviral overexpression of PPAR delta significantly decreased (x-smooth muscle actin (alpha-SMA) levels, indicating a reduced CF to CMF transition. The inhibition of transdifferentiation by PPAR delta 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. Conclusion: Cardiac fibroblast proliferation, fibroblast to myofibroblast differentiation and collagen synthesis were reduced after activation of PPAR delta, suggesting that PPAR delta represents an attractive molecular target for attenuating cardiac fibrosis. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.