title: Activation of PPARdelta inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts.
abstract: 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 (PPARalpha, delta, and gamma) to attenuate cardiac fibroblast proliferation, fibroblast (CF) to myofibroblast (CMF) transdifferentiation, and collagen synthesis was investigated.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
authors.forename: Birgit E J
authors.initials: BE
authors.lastname: Teunissen
authors.forename: Pascal J H
authors.initials: PJ
authors.lastname: Smeets
authors.forename: Peter H M
authors.initials: PH
authors.lastname: Willemsen
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
authors.forename: Ger J
authors.initials: GJ
authors.lastname: Van der Vusse
authors.forename: Marc
authors.initials: M
authors.lastname: Van Bilsen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047493:PPAR alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014161:Transduction, Genetic / Q000379:methods
chemical_list: C425931:GW 501516; D008024:Ligands; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C006253:pirinixic acid; D003094:Collagen