on February 12, 2009
Published online before print February 12, 2009, doi: 10.1161/ATVBAHA.108.178558
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Submitted on March 14, 2008
Accepted on February 3, 2009
PDGF-A, -C, and -D but not PDGF-B Increase TGF-
1 and Chronic Rejection in Rat Cardiac Allografts
Raimo Tuuminen *;
From the Cardiopulmonary Research Group, Transplantation Laboratory (R.T., A.I.N., R.K., M.A.I.K., P.K.K., K.B.L.), University of Helsinki and Helsinki University Central Hospital; the Department of Cardiothoracic Surgery (K.B.L.), Helsinki University Central Hospital; and the Molecular Cancer Biology Laboratory (J.S., K.P., K.A.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
* To whom correspondence should be addressed. E-mail: Raimo.Tuuminen{at}Helsinki.Fi.
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.
Methods and Results—PDGFR-
mRNA was upregulated in acutely-rejecting, and PDGF-A and PDGF-C mRNA in chronically-rejecting cardiac¢hatn allografts. In acute rejection, PDGFR- 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-
1 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-1 pathway. Inhibition of signaling of all PDGF-ligands except that of PDGF-B may thus be needed to inhibit chronic rejection in cardiac allografts.
Key words: smooth muscle cell • arteriosclerosis • fibrosis • transplantation • gene transfer