The effect of platelet-derived growth factor ligands in rat cardiac allograft vasculopathy and fibrosis.
BACKGROUND
In chronic rejection, parenchymal fibrosis and cardiac allograft vasculopathy (CAV) characterized by neointimal growth are the leading causes of graft loss for heart transplant recipients. During alloimmune responses a variety of cytokines, adhesion proteins, and growth factors, such as platelet-derived growth factor (PDGF), are up-regulated. The PDGF family (AA, AB, BB, CC, DD), which acts mainly on connective tissue cells, is considered to be a potent mitogenic and chemotactic factor for fibroblasts and vascular smooth muscle cells. In this study, we evaluated the effects of PDGF ligands in chronic rejection.


METHODS
Heterotopic heart transplantations were performed between fully major histocompatability complex-mismatched Dark Agouti to Wistar Furth rats receiving cyclosporine immunosuppression. Allograft coronary arteries were perfused with a recombinant adeno-associated virus (AAV) encoding enhanced green fluorescence protein (EGFP) as a control gene or PDGF-A, -B, -C, -D. Allografts were harvested at 100 days for morphometric analysis of CAV and fibrosis.


RESULTS
AAV-mediated transgene expression was detected by EGFP immunoreactivity across the graft section (at 100 days) in AAV EGFP-perfused allografts. AAV PDGF-A, -C, and -D perfusion resulted in accelerated CAV and fibrosis. In contrast, AAV PDGF-B perfusion did not induce arteriosclerotic changes or fibrosis in cardiac allografts.


CONCLUSIONS
AAV PDGF-A, -C, and -D overexpression accelerated the development of chronic rejection, whereas PDGF-B did not. Our results suggested that more targeted therapy with monoclonal antibodies blocking the active sites of PDGF-A, -C, and -D may produce beneficial effects on heart transplant survival.
Tuuminen
R
R
Transplant Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Nykänen
A
A
Keränen
M A
MA
Krebs
R
R
Alitalo
K
K
Koskinen
P K
PK
Lemström
K B
KB
D000818:Animals; D003327:Coronary Disease / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics; D005355:Fibrosis; D016027:Heart Transplantation / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D011183:Postoperative Complications / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous; D014652:Vascular Diseases
D010982:Platelet-Derived Growth Factor