Intracoronary AAV2-mediated gene transfer of PDGF-A, -C, and -D, but not PDGF-B, significantly upregulated profibrotic TGF-beta1 mRNA and accelerated cardiac fibrosis and arteriosclerosis in rats.
Does AAV2-mediated gene transfer of specific PDGF ligands increase TGF-beta1 and chronic rejection in rat cardiac allografts?
PDGF-A, -C, and -D, but not PDGF-B, mediate profibrotic and proarteriosclerotic effects in rat cardiac allografts via the TGF-beta1 pathway, suggesting targeted inhibition may prevent chronic rejection.
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-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 et al. (Fri,) conducted a other in Cardiac allograft chronic rejection. AAV2-mediated PDGF-A, -B, -C, and -D gene transfer was evaluated on Cardiac allograft inflammation, fibrosis, and arteriosclerosis. Intracoronary AAV2-mediated gene transfer of PDGF-A, -C, and -D, but not PDGF-B, significantly upregulated profibrotic TGF-beta1 mRNA and accelerated cardiac fibrosis and arteriosclerosis in rats.
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