Local delivery of platelet-derived growth factor receptor-specific tyrphostin inhibits neointimal formation in rats

Ilia Fishbein, Johannes Waltenberger, Shmuel Banai, Laura Rabinovich, Michael Chorny, Alexander Levitzki, Aviv Gazit, Rita Huber, Ulrike Mayr, S. David Gertz, Gershon Golomb*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Signal transduction through the platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) system is involved in the process of postangioplasty restenosis. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases. We assessed the antiproliferative effects of PDGFRβ-specific tyrphostin AG-1295 in vitro and in vivo. AG-1295 significantly inhibited rat smooth muscle cell growth stimulated by PDGF-BB or FCS. This antiproliferative effect was paralleled by reversible reduction of the total phosphotyrosine level and the degree of PDGFRβ phosphorylation by the drug in vitro. Local sustained delivery of the drug from perivascularly implanted polymeric matrices resulted in focal AG-1295 levels of 711 and 29.1 ng/mg of dry arterial tissue 1 and 14 days after implantation in rats. AG-1295 delivered from polymeric matrices resulted in a 35% reduction of neointimal formation on day 14 after balloon injury in the rat carotid model. Tyrosine phosphorylation of certain transduction proteins in arterial tissue extracts was significantly upregulated by balloon injury on day 3 but was essentially returned to or below basal levels 14 days after injury. Tyrphostin treatment decreased tyrosine phosphorylation at both time points below the basal levels. Moreover, the enhancement of PDGFRβ expression 3 and 14 days after arterial injury was strongly inhibited by AG- 1295 treatment. It can be concluded that AG-1295 reduces neointimal formation by inhibiting PDGFβ-triggered tyrosine phosphorylation.

Original languageEnglish
Pages (from-to)667-676
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume20
Issue number3
DOIs
StatePublished - Mar 2000

Keywords

  • Controlled release
  • Platelet-derived growth factor
  • Protein tyrosine kinase
  • Restenosis
  • Tyrphostins

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