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 (PD GF)-AA, -R alpha, and -R beta in intimal cells correlates with the developm ent of cardiac allograft arteriosclerosis, a condition for which there is l ittle or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease. Methods and 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(a)) 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 backgro und cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesi ons in rat cardiac and aortic allograft recipients. When rat coronary smoot h muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1 beta or tumor necrosis factor-alpha, CGP 53716 significan tly inhibited only AA-ligand-induced but not BB-ligand-induced replication. Concomitantly, in quantitative reverse transcriptase-polymerase chain reac tion, interleukin-1 beta or tumor necrosis factor-alpha stimulation specifi cally upregulated the expression of PDGF-R alpha mRNA but not of other liga nd or receptor genes in cultured smooth muscle cells. Conclusions-We conclude that a PDGF-AA/R alpha-dependent cycle is induced i n the generation of allograft arteriosclerosis that may be inhibited by blo cking of signaling downstream of PDGF-R.