Local delivery of platelet-derived growth factor receptor-specific tyrphostin inhibits neointimal formation in rats
Local delivery of platelet-derived growth factor receptor-specific tyrphostin inhibits neointimal formation in rats
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DOI：
10.1161/01.atv.20.3.667
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发表时间：
2000-03-01
影响因子：
8.7
通讯作者：
Colomb, G
中科院分区：
文献类型：
--
作者：
Fishbein, I;Waltenberger, J;Colomb, G
通过血小板衍生生长因子(PDGF)/PDGF受体（PDGFR）系统的信号转导参与血管成形术后再狭窄的过程。酪氨酸肽是蛋白酪氨酸激酶的低分子量抑制剂；我们评估了PDGFR β特异性tyrphostin AG-1295在体外和体内的抗增殖作用。AG-1295显著抑制PDGF-BB或FCS刺激的大鼠平滑肌细胞生长。这种抗增殖作用与该药物在体外可逆转地降低总磷酪氨酸水平和PDGFR β磷酸化程度相平行。从血管周围植入的聚合物基质中局部持续递送药物，在植入后1天和14天，大鼠干动脉组织的局灶性AG-1295水平分别为711和29.1 ng/mg。在大鼠颈动脉球囊损伤后第14天，聚合基质递送的AG-1295导致新内膜形成减少35%。球囊损伤后第3天，动脉组织提取物中某些转导蛋白的酪氨酸磷酸化水平显著上调，但在损伤后第14天基本恢复到或低于基础水平。Tyrphostin处理使酪氨酸磷酸化在两个时间点都低于基础水平。此外，在动脉损伤后第3天和第14天，AG-1295对PDGFR β表达的增强作用被强烈抑制，这表明AG-1295通过抑制PDGF β触发的酪氨酸磷酸化来减少新内膜的形成。
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 PDGFR beta-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 PDGFR beta 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 PDGFR beta 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 PDGF beta-triggered tyrosine phosphorylation.