Copyright © 2007, European Society of Cardiology
Activation of PPAR
inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts
aDepartment of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
bHubrecht Laboratory and Interuniversity Cardiology Institute of the Netherlands, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
* Corresponding author. Tel.: +31 43 3881204; fax: +31 43 3884166. marc.vanbilsen{at}fys.unimaas.nl
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
, 
, and 
) to attenuate cardiac fibroblast proliferation, fibroblast (CF) to myofibroblast (CMF) transdifferentiation, and collagen synthesis was investigated.
Methods and results PPAR was found to be the most abundant isoform in both CF and CMF. Only the PPAR ligand GW501516, but not PPAR ligand Wy-14,643 or PPAR ligand rosiglitazone, significantly increased PPAR-dependent promoter activity and expression of the PPAR-responsive gene UCP2 (
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 PPAR ligand or adenoviral overexpression of PPAR significantly decreased -smooth muscle actin (-SMA) levels, indicating a reduced CF to CMF transition. The inhibition of transdifferentiation by PPAR correlated with an increase in PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome ten) expression. 3H-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, suggesting that PPAR represents an attractive molecular target for attenuating cardiac fibrosis.
KEYWORDS Cardiac fibroblast; Cardiac myofibroblast; Peroxisome Proliferator-Activated Receptor (PPAR); PPAR; Proliferation; Transdifferentiation; Collagen
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