Big Mitogen-Activated Protein Kinase 1 (BMK1)/Extracellular Signal Regulated Kinase 5 (ERK5) Is Involved in Platelet-Derived Growth Factor (PDGF)−Induced Vascular Smooth Muscle Cell Migration
Big Mitogen-Activated Protein Kinase 1 (BMK1)/Extracellular Signal Regulated Kinase 5 (ERK5) Is Involved in Platelet-Derived Growth Factor (PDGF)−Induced Vascular Smooth Muscle Cell Migration
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DOI：
10.1291/hypres.30.1107
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发表时间：
2007-11
影响因子：
5.4
通讯作者：
Yuki Izawa;M. Yoshizumi;K. Ishizawa;Y. Fujita;Shuji Kondo;S. Kagami;K. Kawazoe;K. Tsuchiya;S. Tomita;T. Tamaki
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文献类型：
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作者：
Yuki Izawa;M. Yoshizumi;K. Ishizawa;Y. Fujita;Shuji Kondo;S. Kagami;K. Kawazoe;K. Tsuchiya;S. Tomita;T. Tamaki
大丝裂原活化蛋白激酶1 (BMK1)，也被称为细胞外信号调节激酶5 (ERK5)，是新发现的丝裂原活化蛋白激酶家族的成员。近年来，多项研究表明BMK1在心血管疾病的发病机制中起重要作用。为了阐明BMK1在血管重构过程中的病理生理意义，我们探讨了BMK1在血管平滑肌细胞（VSMCs）中激活的分子机制。从免疫共沉淀和免疫印迹分析的结果中，我们发现血小板衍生生长因子（PDGF），一种已知的强效丝裂原，激活BMK1并触发大鼠主动脉平滑肌细胞（RASMCs）中Gab1 - SHP-2的相互作用。通过转染SHP-2- c /S突变体来消除SHP-2磷酸酶活性，抑制pdgf刺激的BMK1激活。表达显性阴性MEK5α的腺病毒载体可将pdgf刺激的BMK1激活抑制到控制水平，感染MEK5α可抑制pdgf诱导的RASMC迁移。此外，我们观察到损伤小鼠股动脉中BMK1激活增加。这些发现表明，BMK1激活通过Gab1 - SHP-2相互作用导致PDGF诱导的VSMC迁移，并且BMK1介导的VSMC迁移可能在血管重塑的发病机制中发挥作用。
Big mitogen-activated protein kinase 1 (BMK1), also known as extracellular signal–regulated kinase 5 (ERK5), is a newly identified member of the mitogen-activated protein (MAP) kinase family. Recently, several studies have suggested that BMK1 plays an important role in the pathogenesis of cardiovascular disease. To clarify the pathophysiological significance of BMK1 in the process of vascular remodeling, we explored the molecular mechanisms of BMK1 activation in vascular smooth muscle cells (VSMCs). From the results of co-immunoprecipitation and immunoblotting analyses, it was found that platelet-derived growth factor (PDGF), a known potent mitogen, activated BMK1 and triggered the Gab1−SHP-2 interaction in rat aortic smooth muscle cells (RASMCs). The abrogation of SHP-2 phosphatase activity by transfection of the SHP-2-C/S mutant suppressed PDGF-stimulated BMK1 activation. Infection with an adenoviral vector expressing dominant-negative MEK5α, which can suppress PDGF-stimulated BMK1 activation to the control level, inhibited PDGF-induced RASMC migration. Moreover, we observed an increase of BMK1 activation in injured mouse femoral arteries. From these findings, it is suggested that BMK1 activation leads to VSMC migration induced by PDGF via Gab1−SHP-2 interaction, and that BMK1-mediated VSMC migration may play a role in the pathogenesis of vascular remodeling.