Nifedipine interferes with migration of vascular smooth muscle cells via inhibition of Pyk2-Src axis.
Nifedipine interferes with migration of vascular smooth muscle cells via inhibition of Pyk2-Src axis.
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DOI：
10.5551/jat.e422
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发表时间：
2009-06
影响因子：
4.4
通讯作者：
N. Soe;T. Ishida;M. Ishida;Mariko Sawano;Keiko Abe;N. Miho;K. Chayama;Y. Kihara;M. Yoshizumi
中科院分区：
文献类型：
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作者：
N. Soe;T. Ishida;M. Ishida;Mariko Sawano;Keiko Abe;N. Miho;K. Chayama;Y. Kihara;M. Yoshizumi
目的钙通道阻滞剂（CCBs）抑制血管平滑肌细胞（VSMC）迁移的机制尚不清楚。本研究的目的是表征CCBs抑制VSMC迁移的信号转导机制。方法和结果硝苯地平能有效抑制血小板源性生长因子（PDGF）诱导的趋化性、I型胶原诱导的趋触性和创伤诱导的人主动脉VSMC迁移。此外，硝苯地平抑制PDGF诱导的膜皱褶和板状伪足的形成。PDGF诱导的VSMC迁移被PP 2显著抑制，PP 2是Src激酶家族的选择性抑制剂，并且也被激酶失活的Src的表达显著抑制，这表明Src是VSMC迁移所需的。硝苯地平还抑制PDGF诱导的Src活化（30 μ M时为60+/-4%）和Cas、桩蛋白和coronin（Src的肌动蛋白相关底物）的酪氨酸磷酸化。RNA干扰诱导的Ca（2+）依赖性酪氨酸激酶Pyk 2的敲低导致对PDGF诱导的Src激活和迁移的抑制。最后，硝苯地平以剂量依赖性方式抑制PDGF诱导的Pyk 2活化。结论硝苯地平通过抑制Pyk 2-Src轴和抑制肌动蛋白重构过程，包括膜皱褶和板状伪足的形成，干扰VSMC迁移。
AIM Calcium channel blockers (CCBs) inhibit the migration of vascular smooth muscle cells (VSMC) by mechanisms that remain poorly understood. The purpose of the present study was to characterize the signaling mechanisms by which CCBs inhibit VSMC migration. METHODS AND RESULTS Nifedipine potently inhibited platelet-derived growth factor (PDGF)-induced chemotaxis, collagen I-induced haptotaxis, and wound-induced migration of human aortic VSMC. In addition, nifedipine inhibited PDGF-induced membrane ruffling and lamellipodium formation. PDGF-induced VSMC migration was significantly inhibited by PP2, a selective inhibitor of the Src kinase family, and was also significantly inhibited by the expression of kinase-inactive Src, suggesting that Src is required for VSMC migration. Nifedipine also inhibited PDGF-induced Src activation (by 60+/-4% with 30 microM) and tyrosinephosphorylation of Cas, paxillin, and cortactin, which are actin-associated substrates of Src. RNA interference-induced knockdown of the Ca(2+)-dependent tyrosine kinase, Pyk2, resulted in inhibition of PDGF-induced Src activation and migration. Finally, nifedipine inhibited PDGF-induced Pyk2 activation in a dose-dependent manner. CONCLUSION These data suggest that nifedipine interferes with VSMC migration via inhibition of the Pyk2-Src axis and inhibition of actin remodeling processes, including membrane ruffling and lamellipodium formation.