Inhibition of aortic allograft vasculopathy by local delivery of platelet-derived growth factor receptor tyrosine-kinase blocker AG-1295

Matthias Karck*, Rolf Meliss, Michael Hestermann, Michael Mengel, Klaus Pethig, Alexander Levitzki, Shmuel Banai, Gershon Golomb, Ilia Fishbein, Michael Chorny, Axel Haverich

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background. Signal transduction through the platelet-derived growth factor (PDGF)/PDGF-receptor (PDGFR) system has been linked to vascular smooth muscle cell migration and proliferation leading to allograft vasculopathy. This study describes the effect of the tyrphostin AG-1295, a specific PDGFR tyrosinekinase inhibitor, on neointimal formation in this disease. Methods and Results. Rat aortic allografts transplanted from dark agouti (RT1av1) donors to Wistar-Furth (RT1u) recipients were assessed in a new treatment model for local drug delivery from polymeric carrier matrices precoated with AG-1295. Matrices were wrapped around the graft immediately after transplantation. The recipients received no background immunosuppression. At day 80 posttransplantation, intimal thickness in AG-1295-treated grafts was reduced when compared to controls (11.8±9.1% intimal thickness vs. 23.7±6.4% intimal thickness; P=0.042). This finding corresponded to inhibition of intimal PDGFR-β expression in AG-1295-treated grafts at day 20 posttransplantation (P=0.029 vs. allogeneic controls). Conclusions. The tyrphostin AG-1295 reduces neointimal formation in aortic allograft vasculopathy by inhibition of PDGFR-β-triggered tyrosine phosphorylation. Local drug release of specific tyrosine-kinase inhibitors from perivascularly co-implanted polymeric carrier matrices is effective in the prophylaxis of allograft vasculopathy under selected experimental conditions.

Original languageEnglish
Pages (from-to)1335-1341
Number of pages7
JournalTransplantation
Volume74
Issue number9
DOIs
StatePublished - 15 Nov 2002

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