title: PDGF-A, -C, and -D but not PDGF-B increase TGF-beta1 and chronic rejection in rat cardiac allografts.
abstract: OBJECTIVE
  Chronic rejection is the main reason for the poor long-term survival of heart transplant recipients and is characterized by cardiac allograft inflammation, fibrosis, and arteriosclerosis. We examined the specific roles of different platelet-derived growth factor (PDGF) ligands (A-D)--potent mesenchymal cell mitogens--in rat cardiac allografts.
  
  
  RESULTS
  PDGFR-alpha mRNA was upregulated in acutely-rejecting, and PDGF-A and PDGF-C mRNA in chronically-rejecting cardiac centhatn allografts. In acute rejection, PDGFR-alpha immunoreactivity increased in the media of arteries. In chronically-rejecting allografts, immunoreactivity of all PDGF ligands and receptors--except that of PDGF-B ligand--was found in the intima of arteries, and the expression of PDGF-A and PDGF-C was seen in cardiomyocytes. Intracoronary adeno-associated virus-2 (AAV2)-mediated PDGF-A and -D gene transfer enhanced cardiac allograft inflammation. AAV2-PDGF-A, AAV2-PDGF-C, and AAV2-PDGF-D significantly upregulated profibrotic TGF-beta1 mRNA and accelerated cardiac fibrosis and arteriosclerosis. In contrast, AAV2-PDGF-B did not aggravate chronic rejection.
  
  
  CONCLUSIONS
  We found that alloimmune response induces PDGF-A, PDGF-C, and PDGF-D expression in the graft vasculature. PDGF-A, PDGF-C, and PDGF-D mediated profibrotic and proarteriosclerotic effects in transplanted hearts involving the TGF-beta1 pathway. Inhibition of signaling of all PDGF-ligands except that of PDGF-B may thus be needed to inhibit chronic rejection in cardiac allografts.
authors.affiliation: Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Raimo.Tuuminen@Helsinki.Fi
authors.forename: Raimo
authors.initials: R
authors.lastname: Tuuminen
authors.forename: Antti I
authors.initials: AI
authors.lastname: Nykänen
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.forename: Jarkko
authors.initials: J
authors.lastname: Soronen
authors.forename: Katri
authors.initials: K
authors.lastname: Pajusola
authors.forename: Mikko A I
authors.initials: MA
authors.lastname: Keränen
authors.forename: Petri K
authors.initials: PK
authors.lastname: Koskinen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000276:immunology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014184:Transplantation, Homologous; D015854:Up-Regulation
chemical_list: D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1