Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways.
Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways.
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DOI：
10.1161/circresaha.111.262519
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发表时间：
2012-05-11
影响因子：
20.1
通讯作者：
Schmidt AM
中科院分区：
文献类型：
--
作者：
Touré F;Fritz G;Li Q;Rai V;Daffu G;Zou YS;Rosario R;Ramasamy R;Alberts AS;Yan SF;Schmidt AM
哺乳动物透明相关的微管，mDia 1，管理微管和微丝动力学，同时作为效应器的Rho小GTP结合蛋白在关键的细胞过程，如粘附，胞质分裂，细胞极性和形态发生。晚期糖基化终产物受体（receptor for advanced glycation endproducts，RECEPTOR）的胞浆结构域与mDia 1的胞浆同源性1（FH 1）结构域结合; mDia 1是转化细胞中RECEPTOR配体诱导的细胞迁移所必需的。由于血管重塑的一个关键机制是诱导平滑肌细胞迁移，我们测试了mDia 1在这一过程中的作用。我们报告，内皮剥脱损伤小鼠股动脉显着上调mDia 1 mRNA转录和蛋白质在受伤的血管，特别是在血管平滑肌细胞内的扩张的新生内膜。mDia 1表达的缺失显著减少损伤后病理性新生内膜扩张。在原代鼠主动脉平滑肌细胞中，mDia 1是配体诱导的c-Src膜转位所必需的，这导致Rac 1活化、AKT/GSK 3 β的氧化还原磷酸化和随后的平滑肌细胞迁移。我们的结论是，mDia 1整合氧化和信号转导通路触发，至少部分由β配体，因此调节病理性新生内膜扩张。
The mammalian Diaphanous-related formin, mDia1, governs microtubule and microfilament dynamics while functioning as an effector for Rho small GTP-binding proteins during key cellular processes such as adhesion, cytokinesis, cell polarity and morphogenesis. The cytoplasmic domain of the receptor for advanced glycation endproducts (RAGE) binds to the formin homology 1 (FH1) domain of mDia1; mDia1 is required for RAGE ligand-induced cellular migration in transformed cells. As a key mechanism in vascular remodeling is the induction of smooth muscle cell migration, we tested the role of mDia1 in this process. We report that endothelial denudation injury to the murine femoral artery significantly upregulates mDia1 mRNA transcripts and protein in the injured vessel, particularly in vascular smooth muscle cells within the expanding neointima. Loss of mDia1 expression significantly reduces pathological neointimal expansion consequent to injury. In primary murine aortic smooth muscle cells, mDia1 is required for RAGE ligand-induced membrane translocation of c-Src, which leads to Rac1 activation, redox phosphorylation of AKT/GSK3β and consequent smooth muscle cell migration. We conclude that mDia1 integrates oxidative and signal transduction pathways triggered, at least in part by RAGE ligands, therefore regulates pathological neointimal expansion.