Slingshot isoform-specific regulation of cofilin-mediated vascular smooth muscle cell migration and neointima formation.
Slingshot isoform-specific regulation of cofilin-mediated vascular smooth muscle cell migration and neointima formation.
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DOI：
10.1161/atvbaha.111.232769
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Weber DS
中科院分区：
文献类型：
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作者：
Torres RA;Drake DA;Solodushko V;Jadhav R;Smith E;Rocic P;Weber DS
我们假设，cofilin激活弹弓（SSH）磷酸酶家族的成员是一个关键的机制，调节血管损伤后的VSMC迁移和新生内膜形成。划痕法和改良的Boyden小室法分别用于评估siRNA下调Cofilin和每种弹弓磷酸酶亚型（SSH1、SSH2、SSH3）表达后的VSMC迁移。Cofilin siRNA极大地减弱了VSMC迁移到“伤口”中的能力，并且与未处理的VSMC中的3.5倍增加相比，PDGF诱导的迁移几乎被消除，从而确立了Cofilin在VSMC迁移中的关键作用。在PDGF刺激的VSMC中，Cofilin活化（去磷酸化）增加。因此，我们评估了磷酸酶SSH家族对cofilin激活和VSMC迁移的作用。用SSH1或SSH2 siRNA处理减弱了cofilin激活，而SSH3 siRNA没有影响。只有SSH1 siRNA显著减少伤口愈合和PDGF诱导的VSMC迁移。SSH1（4.7倍）和cofilin（3.9倍）的表达增加球囊损伤与未损伤的颈动脉和表达是普遍的新生内膜。这些研究表明，Cofilin对VSMC迁移的调节是SSH1依赖性的，并且这种机制可能有助于体内血管损伤后新生内膜的形成。
We hypothesized that cofilin activation by members of the slingshot (SSH) phosphatase family is a key mechanism regulating VSMC migration and neoinitima formation following vascular injury. Scratch wound and modified Boyden chamber assays were used to assess VSMC migration following downregulation of the expression of cofilin and each slingshot phosphatase isoforms (SSH1,-2,-3) by siRNA, respectively. Cofilin siRNA greatly attenuated the ability of VSMC migration into the “wound” and PDGF-induced migration was virtually eliminated versus a 3.5-fold increase in non-treated VSMCs, establishing a critical role for cofilin in VSMC migration. Cofilin activation (dephosphorylation) was increased in PDGF-stimulated VSMCs. Thus, we assessed the role of the SSH family of phosphatases on cofilin activation and VSMC migration. Treatment with either SSH1 or SSH2 siRNA attenuated cofilin activation, while SSH3 siRNA had no effect. Only SSH1 siRNA significantly reduced wound healing and PDGF-induced VSMC migration. Both SSH1 (4.7 fold) and cofilin (3.9 fold) expression were increased in balloon injured versus non-injured carotid arteries and expression was prevalent in the neointima. These studies demonstrate that the regulation of VSMC migration by cofilin is SSH1 dependent, and that this mechanism potentially contributes to neointima formation following vascular injury in vivo.