PDGF-A, -C, and -D but not PDGF-B increase TGF-beta1 and chronic rejection in rat cardiac allografts.
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.
Tuuminen
Raimo
R
Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Raimo.Tuuminen@Helsinki.Fi
Nykänen
Antti I
AI
Krebs
Rainer
R
Soronen
Jarkko
J
Pajusola
Katri
K
Keränen
Mikko A I
MA
Koskinen
Petri K
PK
Alitalo
Kari
K
Lemström
Karl B
KB
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
D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1