Novel role of proline-rich nonreceptor tyrosine kinase 2 in vascular wall remodeling after balloon injury.
Novel role of proline-rich nonreceptor tyrosine kinase 2 in vascular wall remodeling after balloon injury.
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DOI：
10.1161/atvbaha.112.253112
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Rao GN
中科院分区：
文献类型：
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作者：
Gadepalli R;Singh NK;Kundumani-Sridharan V;Heckle MR;Rao GN
研究富含脯氨酸的非受体酪氨酸激酶Pyk 2在GPCR激动剂、凝血酶诱导的HASMC生长和迁移以及损伤诱导的血管壁重塑中的作用。凝血酶，GPCR激动剂，激活Pyk2在一个时间依赖性的方式和抑制其刺激衰减凝血酶诱导的HASMC迁移和增殖。凝血酶也依次激活Gab1，p115 RhoGEF，Rac1，RhoA和Pak1，干扰这些分子的刺激减弱凝血酶诱导的HASMC迁移和增殖。此外，腺病毒介导的显性失活Pyk2表达抑制凝血酶诱导的Gab1、p115 RhoGEF、Rac1、RhoA和Pak1刺激。球囊损伤还引起大鼠颈动脉中Pyk 2、Gab1、p115 RhoGEF、Rac 1、RhoA和Pak 1的激活，并且这些反应对显性负性Pyk 2的抑制敏感。此外，Pyk2激活的抑制导致SMC在管腔表面上的募集减少以及它们在内膜区域中的增殖减少，从而抑制新生内膜形成。总之，这些结果首次证明Pyk2在GPCR激动剂凝血酶诱导的HASMC生长和迁移以及球囊损伤诱导的新生内膜形成中起关键作用。
To investigate the role of Pyk2, a proline-rich non-receptor tyrosine kinase, in GPCR agonist, thrombin-induced HASMC growth and migration and injury-induced vascular wall remodeling. Thrombin, a GPCR agonist, activated Pyk2 in a time-dependent manner and inhibition of its stimulation attenuated thrombin-induced HASMC migration and proliferation. Thrombin also sequentially activated Gab1, p115 RhoGEF, Rac1, RhoA and Pak1 and interference with stimulation of these molecules attenuated thrombin-induced HASMC migration and proliferation. In addition, adenovirus-mediated expression of dominant negative Pyk2 inhibited thrombin-induced Gab1, p115 RhoGEF, Rac1, RhoA and Pak1 stimulation. Balloon injury also caused activation of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA and Pak1 in the carotid artery of rat and these responses were sensitive to inhibition by dominant negative Pyk2. Furthermore, inhibition of Pyk2 activation resulted in reduced recruitment of SMC 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 GPCR agonist thrombin-induced HASMC growth and migration as well as balloon injury-induced neointima formation.