TY - JOUR
T1 - Local delivery of platelet-derived growth factor receptor-specific tyrphostin inhibits neointimal formation in rats
AU - Fishbein, Ilia
AU - Waltenberger, Johannes
AU - Banai, Shmuel
AU - Rabinovich, Laura
AU - Chorny, Michael
AU - Levitzki, Alexander
AU - Gazit, Aviv
AU - Huber, Rita
AU - Mayr, Ulrike
AU - Gertz, S. David
AU - Golomb, Gershon
PY - 2000/3
Y1 - 2000/3
N2 - 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.
AB - 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.
KW - Controlled release
KW - Platelet-derived growth factor
KW - Protein tyrosine kinase
KW - Restenosis
KW - Tyrphostins
UR - http://www.scopus.com/inward/record.url?scp=0034016296&partnerID=8YFLogxK
U2 - 10.1161/01.ATV.20.3.667
DO - 10.1161/01.ATV.20.3.667
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C2 - 10712389
AN - SCOPUS:0034016296
SN - 1079-5642
VL - 20
SP - 667
EP - 676
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 3
ER -