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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:691.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

PDGF-A, -C, and -D but not PDGF-B Increase TGF-β1 and Chronic Rejection in Rat Cardiac Allografts

Raimo Tuuminen; Antti I. Nykänen; Rainer Krebs; Jarkko Soronen; Katri Pajusola; Mikko A.I. Keränen; Petri K. Koskinen; Kari Alitalo; Karl B. Lemström

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; Department of Cardiothoracic Surgery (K.B.L.), Helsinki University Central Hospital; Molecular Cancer Biology Laboratory (J.S., K.P., K.A.), Department of Pathology, Haartman Institute, Biomedicum Helsinki and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

Correspondence to Raimo Tuuminen, MD, Transplantation Laboratory, Haartman Institute, PO Box 21 (Haartmaninkatu 3), FI-00014 University of Helsinki, Finland. 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-β1 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-β1 pathway. Inhibition of signaling of all PDGF-ligands except that of PDGF-B may thus be needed to inhibit chronic rejection in cardiac allografts.

Alloimmune response induces PDGF-A, PDGF-C, and PDGF-D in the graft vasculature, and overexpression of these ligands upregulates TGF-β1 mRNA and enhances cardiac fibrosis and arteriosclerotic changes in cardiac allografts. Our results suggest that inhibition of signaling of all PDGF ligands except that of PDGF-B may be needed to inhibit chronic rejection in cardiac allografts.

Key Words: smooth muscle cell • arteriosclerosis • fibrosis • transplantation • gene transfer