Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor.
BACKGROUND
Increased immunoreactivity of platelet-derived growth factor (PDGF)-AA, -Ralpha, and -Rbeta in intimal cells correlates with the development of cardiac allograft arteriosclerosis, a condition for which there is little or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease.


RESULTS
The hypothesis was tested in a rat model of heterotopic cardiac and aortic allografts using dark agouti (AG-B4, RT1(a)) donors and Wistar-Furth (AG-B2, RT1(u)) recipients. The recipients received CGP 53716, a selective PDGF-R protein tyrosine kinase inhibitor, 50 mg. kg-1. d-1, or vehicle for 60 days. Cardiac allograft recipients also received background cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac and aortic allograft recipients. When rat coronary smooth muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1beta or tumor necrosis factor-alpha, CGP 53716 significantly inhibited only AA-ligand-induced but not BB-ligand-induced replication. Concomitantly, in quantitative reverse transcriptase-polymerase chain reaction, interleukin-1beta or tumor necrosis factor-alpha stimulation specifically upregulated the expression of PDGF-Ralpha mRNA but not of other ligand or receptor genes in cultured smooth muscle cells.


CONCLUSIONS
We conclude that a PDGF-AA/Ralpha-dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.
Sihvola
R
R
Cardiopulmonary Research Group of the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, and Novartis Pharma, Basel, Switzerland.
Koskinen
P
P
Myllärniemi
M
M
Loubtchenkov
M
M
Häyry
P
P
Buchdunger
E
E
Lemström
K
K
D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016027:Heart Transplantation / Q000009:adverse effects*; D007375:Interleukin-1 / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011920:Rats, Inbred WF; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C092972:CGP 53716; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D011725:Pyridines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor