Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.
Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2652-61. doi: 10.1161/ATVBAHA.112.253112. Epub 2012 Aug 23.
To investigate the role of Pyk2, a proline-rich nonreceptor tyrosine kinase, in G protein-coupled receptor agonist, thrombin-induced human aortic smooth muscle cell growth and migration, and injury-induced vascular wall remodeling.
Thrombin, a G protein-coupled receptor agonist, activated Pyk2 in a time-dependent manner and inhibition of its stimulation attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. Thrombin also activated Grb2-associated binder protein 1, p115 Rho guanine nucleotide exchange factor, Rac1, RhoA, and p21-activated kinase 1 (Pak1) and interference with stimulation of these molecules attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. In addition, adenovirus-mediated expression of dominant negative Pyk2 inhibited thrombin-induced Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA and Pak1 stimulation. Balloon injury also caused activation of Pyk2, Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA, and Pak1 in the carotid artery of rat, and these responses were sensitive to inhibition by the dominant negative Pyk2. Furthermore, inhibition of Pyk2 activation resulted in reduced recruitment of smooth muscle cells onto the luminal surface and their proliferation in the intimal region leading to suppression of neointima formation.
Together, these results demonstrate for the first time that Pyk2 plays a crucial role in G protein-coupled receptor agonist thrombin-induced human aortic smooth muscle cell growth and migration, as well as balloon injury-induced neointima formation.
研究富含脯氨酸的非受体酪氨酸激酶 Pyk2 在 G 蛋白偶联受体激动剂凝血酶诱导的人主动脉平滑肌细胞生长和迁移以及损伤诱导的血管壁重构中的作用。
凝血酶，一种 G 蛋白偶联受体激动剂，以时间依赖性方式激活 Pyk2，抑制其刺激可减弱凝血酶诱导的人主动脉平滑肌细胞迁移和增殖。凝血酶还激活了 Grb2 相关结合蛋白 1、p115Rho 鸟苷酸交换因子、Rac1、RhoA 和 p21 激活激酶 1（Pak1），干扰这些分子的刺激可减弱凝血酶诱导的人主动脉平滑肌细胞迁移和增殖。此外，腺病毒介导的显性负 Pyk2 表达抑制了凝血酶诱导的 Grb2 相关结合蛋白 1、p115Rho 鸟苷酸交换因子、Rac1、RhoA 和 Pak1 刺激。球囊损伤也导致大鼠颈动脉中 Pyk2、Grb2 相关结合蛋白 1、p115Rho 鸟苷酸交换因子、Rac1、RhoA 和 Pak1 的激活，这些反应对显性负 Pyk2 的抑制敏感。此外，抑制 Pyk2 激活可导致平滑肌细胞向管腔表面募集减少和内膜区域增殖减少，从而抑制新生内膜形成。
这些结果首次表明，Pyk2 在 G 蛋白偶联受体激动剂凝血酶诱导的人主动脉平滑肌细胞生长和迁移以及球囊损伤诱导的新生内膜形成中发挥关键作用。
