Although the involvement of Rho proteins in the pathogenesis of vascular diseases is well studied, little is known about the role of their upstream regulators, the Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular wall remodeling. We found that, among the RhoGEFs tested, MCP1 induced tyrosine phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or leukemia-associated RhoGEF in human aortic smooth muscle cells (HASMCs). Moreover, p115 RhoGEF inhibition suppressed MCP1-induced HASMC migration and proliferation. Consistent with these observations, balloon injury (BI) induced p115 RhoGEF tyrosine phosphorylation in rat common carotid arteries, and siRNA-mediated down-regulation of its levels substantially attenuated BI-induced smooth muscle cell migration and proliferation, resulting in reduced neointima formation. Furthermore, depletion of p115 RhoGEF levels also abrogated MCP1- or BI-induced Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling, which, as we reported previously, is involved in vascular wall remodeling. Our findings also show that protein kinase N1 (PKN1) downstream of Rac1-cyclin D1/CDK6 and upstream of CDK4-PAK1 in the p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling axis is involved in the modulation of vascular wall remodeling. Of note, we also observed that CCR2-Gi/o-Fyn signaling mediates MCP1-induced p115 RhoGEF and Rac1 GTPase activation. These findings suggest that p115 RhoGEF is critical for MCP1-induced HASMC migration and proliferation in vitro and for injury-induced neointima formation in vivo by modulating Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling.

译文

尽管对Rho蛋白参与血管疾病的发病机理进行了很好的研究,但对其上游调节剂Rho鸟嘌呤核苷酸交换因子 (rhoiefs) 的作用知之甚少。在这里,我们试图鉴定参与单核细胞趋化蛋白1 (MCP1) 诱导的血管壁重塑的RhoGEFs。我们发现,在测试的RhoGEFs中,MCP1诱导人主动脉平滑肌细胞 (HASMCs) 中p115 RhoGEF的酪氨酸磷酸化,但不诱导PDZ RhoGEF或与白血病相关的RhoGEF的酪氨酸磷酸化。此外,p115 rhoge抑制抑制了MCP1-induced HASMC的迁移和增殖。与这些观察结果一致,球囊损伤 (BI) 在大鼠颈总动脉中诱导了p115 RhoGEF酪氨酸磷酸化,而siRNA介导的其水平下调大大减弱了BI诱导的平滑肌细胞迁移和增殖,从而减少了新内膜的形成。此外,p115 RhoGEF水平的耗竭也消除了MCP1或BI诱导的Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号传导,正如我们先前报道的那样,这与血管壁重塑有关。我们的发现还表明,Rac1-cyclin D1/CDK6下游和p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号轴CDK4-PAK1上游的蛋白激酶N1 (PKN1) 参与了血管壁重塑的调节。值得注意的是,我们还观察到CCR2-Gi/o-Fyn信号介导MCP1-induced p115 rhoge和rac1gtpase激活。这些发现表明,p115 RhoGEF对于MCP1-induced HASMC在体外迁移和增殖以及通过调节Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1信号传导在体内损伤诱导的新内膜形成至关重要。

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