Abe J, Deguchi J, Matsumoto T, Takuwa N, Noda M, Ohno M, Makuuchi M, Kurokawa K, Takuwa Y
Department of Cardiovascular Biology, Faculty of Medicine, University of Tokyo, Japan.
Circulation. 1997 Sep 16;96(6):1906-13. doi: 10.1161/01.cir.96.6.1906.
Growth factors such as platelet-derived growth factor (PDGF) have been postulated to be important mediators of neointimal formation in balloon-injured artery. Binding of growth factors to their receptors activates intrinsic receptor tyrosine kinase, resulting in tyrosine phosphorylation of receptors themselves and cellular substrate proteins. We investigated in vivo activities of growth factors by determining the extent of tyrosine phosphorylation of growth factor receptors and substrate proteins in injured artery.
Rat balloon-injured carotid artery was analyzed for phosphotyrosine content of PDGF alpha- and beta-receptors, epidermal growth factor (EGF) receptors, and insulin receptor substrate-1 (IRS-1) by immunoprecipitation and anti-phosphotyrosine Western blot. The development of intimal thickening after deendothelializing balloon catheterization of rat carotid artery was accompanied by transient twofold to threefold increases in the extent of tyrosyl phosphorylation of PDGF alpha- and beta-receptors but not EGF receptor or IRS-1. The AT1 angiotensin II (Ang II) receptor antagonist TCV-116 markedly inhibited both tyrosyl phosphorylation of PDGF alpha- and beta-receptors and intimal thickening. The AT1 antagonist reduced mRNA levels of both PDGF-A and -B chains in injured arteries.
The present study provides direct evidence for increased PDGF activities in injured artery in situ and the involvement of Ang II in stimulated activation of PDGF receptors. These results are consistent with the pathogenetic role for PDGF in intimal thickening.
血小板衍生生长因子（PDGF）等生长因子被认为是球囊损伤动脉内膜增生的重要介质。生长因子与其受体结合会激活内在受体酪氨酸激酶，导致受体自身及细胞底物蛋白的酪氨酸磷酸化。我们通过测定损伤动脉中生长因子受体和底物蛋白的酪氨酸磷酸化程度，研究了生长因子的体内活性。
采用免疫沉淀和抗磷酸酪氨酸蛋白质印迹法，分析大鼠球囊损伤颈动脉中PDGFα受体、β受体、表皮生长因子（EGF）受体和胰岛素受体底物-1（IRS-1）的磷酸酪氨酸含量。大鼠颈动脉去内皮球囊导管插入术后内膜增厚的过程中，PDGFα受体和β受体的酪氨酸磷酸化程度短暂增加了两倍至三倍，而EGF受体或IRS-1未出现这种情况。AT1血管紧张素II（Ang II）受体拮抗剂TCV-116显著抑制了PDGFα受体和β受体的酪氨酸磷酸化以及内膜增厚。该AT1拮抗剂降低了损伤动脉中PDGF-A和-B链的mRNA水平。
本研究为损伤动脉原位PDGF活性增加以及Ang II参与刺激PDGF受体激活提供了直接证据。这些结果与PDGF在内膜增厚中的致病作用相符。
