The Actin-Binding Protein Girdin and Its Akt-Mediated Phosphorylation Regulate Neointima Formation After Vascular Injury
The Actin-Binding Protein Girdin and Its Akt-Mediated Phosphorylation Regulate Neointima Formation After Vascular Injury
复制标题
DOI：
10.1161/circresaha.110.236174
复制
发表时间：
2011-05-13
影响因子：
20.1
通讯作者：
Murohara, Toyoaki
中科院分区：
文献类型：
--
作者：
Miyake, Hiroshi;Maeda, Kengo;Murohara, Toyoaki
基本原理：血管平滑肌细胞（vascular smooth muscle cells，VSMCs）的迁移和增殖在血管重构过程中起着重要作用。我们以前的研究表明，Akt底物Girdin在血管平滑肌细胞和内皮细胞中表达，是出生后血管生成所必需的。然而，Girdin及其Akt介导的磷酸化在VSMCs中的功能及其在血管重塑中的体内作用仍有待阐明。目的：我们利用培养的VSMCs和血管重塑动物模型研究Girdin及其Akt介导的磷酸化的功能。通过RNA干扰耗尽Girdin破坏了VSMCs中肌动蛋白细胞骨架的重排，导致细胞迁移受损。Girdin的缺失也抑制了VSMC的增殖。在大鼠模型中，球囊损伤后颈动脉新生内膜中Girdin表达高度上调，其1416位丝氨酸磷酸化。携带针对Girdin的短发夹RNA的腺病毒的引入减弱了VSMCs的增殖和新生内膜形成，而不影响再内皮化。此外，我们发现在Girdin S1416 A基因敲入小鼠中，股线损伤后新生内膜形成显著减弱，其中Girdin的Akt磷酸化位点发生突变，从而表明Girdin磷酸化在血管重塑中起主要作用。这些发现表明Girdin及其Akt介导的磷酸化在VSMCs的迁移和增殖以及血管重塑中起重要作用，使Akt/Girdin信号通路成为开发血管疾病新疗法的潜在靶点。(Circ Res. 2011;108：1170-1179）。
Rationale: It is well established that the migration and proliferation of vascular smooth muscle cells (VSMCs) have major roles in the vascular remodeling process. Our previous study showed that the Akt substrate Girdin, which is expressed in VSMCs and endothelial cells, is essential for postnatal angiogenesis. However, the function of Girdin and its Akt-mediated phosphorylation in VSMCs and their in vivo roles in vascular remodeling remain to be elucidated.Objective: We investigated the function of Girdin and its Akt-mediated phosphorylation using cultured VSMCs and animal models of vascular remodeling.Methods and Results: The depletion of Girdin by RNA interference disrupted the rearrangement of the actin cytoskeleton in VSMCs, resulting in impaired cell migration. The depletion of Girdin also inhibited VSMC proliferation. Girdin expression was highly upregulated and its serine at position 1416 was phosphorylated in the neointima of carotid arteries after balloon injury in a rat model. The introduction of an adenovirus harboring short hairpin RNA against Girdin attenuated the proliferation of VSMCs and neointima formation without affecting reendothelialization. Furthermore, we found that neointima formation after femoral wire injury was significantly attenuated in Girdin S1416A knock-in mice, in which the Akt phosphorylation site of Girdin was mutated, thus indicating a major role for Girdin phosphorylation in vascular remodeling.Conclusions: These findings indicate that Girdin and its Akt-mediated phosphorylation have major roles in the migration and proliferation of VSMCs and vascular remodeling, making the Akt/Girdin signaling pathway a potential target for the development of new therapeutics for vascular diseases. (Circ Res. 2011;108:1170-1179.)