miR-155-dependent regulation of mammalian sterile 20-like kinase 2 (MST2) coordinates inflammation, oxidative stress and proliferation in vascular smooth muscle cells
miR-155-dependent regulation of mammalian sterile 20-like kinase 2 (MST2) coordinates inflammation, oxidative stress and proliferation in vascular smooth muscle cells
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哺乳动物不育 20 样激酶 2 (MST2) 的 miR-155 依赖性调节可协调血管平滑肌细胞的炎症、氧化应激和增殖。
DOI：
10.1016/j.bbadis.2015.04.012
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发表时间：
2015-07-01
影响因子：
6.2
通讯作者：
Wen, Jin-kun
中科院分区：
文献类型：
--
作者：
Yang, Zhan;Zheng, Bin;Wen, Jin-kun
在血管损伤的反应中，炎症、氧化应激和细胞增殖通常同时发生在血管组织中。我们以前观察到，参与增殖和炎症的microRNA-155（miR-155）参与新生内膜增生;然而，它调节这些过程的分子机制在很大程度上仍然未知。在这项研究中，我们观察到，血管平滑肌细胞（VSMC）增殖和新生内膜形成线损伤的股动脉减少的miR-155的损失和增加的miR-155的增益。在培养的VSMC中也观察到miR-155的增殖作用。值得注意的是，在miR-155（-/-）小鼠的损伤动脉中，miR-155靶蛋白哺乳动物无菌20样激酶2（MST 2）的表达增加。miR-155通过促进RAF原癌基因丝氨酸/苏氨酸蛋白激酶（Raf-1）和丝裂原活化蛋白激酶激酶（MEK）之间的相互作用并刺激炎症和氧化应激反应，直接抑制MST 2，从而激活细胞外信号调节激酶（ERK）通路;这些作用共同导致VSMC增殖和血管重塑。我们的数据显示，MST 2通过改变MEK与Raf-1和MST 2在血管损伤中的相互作用来介导miR-155促进的炎症和氧化应激反应。因此，抑制内源性miR-155可能是血管损伤和重塑的一种新的治疗策略。(C)2015爱思唯尔B. V.保留所有权利。
In response to vascular injury, inflammation, oxidative stress, and cell proliferation often occur simultaneously in vascular tissues. We previously observed that microRNA-155 (miR-155), which is implicated in proliferation and inflammation is involved in neointimal hyperplasia; however, the molecular mechanisms by which it regulates these processes remain largely unknown. In this study, we observed that vascular smooth muscle cell (VSMC) proliferation and neointimal formation in wire-injured femoral arteries were reduced by the loss of miR-155 and increased by the gain of miR-155. The proliferative effect of miR-155 was also observed in cultured VSMCs. Notably, expression of the miR-155-target protein mammalian sterile 20-like kinase 2 (MST2) was increased in the injured arteries of miR-155(-/-) mice. miR-155 directly repressed MST2 and thus activated the extracellular signal-regulated kinase (ERK) pathway by promoting an interaction between RAF protooncogene serine/threonine-protein kinase (Raf-1) and mitogen-activated protein kinase kinase (MEK) and stimulating inflammatory and oxidative stress responses; together, these effects lead to VSMC proliferation and vascular remodeling. Our data reveal that MST2 mediates miR-155-promoted inflammatory and oxidative stress responses by altering the interaction of MEK with Raf-1 and MST2 in response to vascular injury. Therefore, suppression of endogenous miR-155 might be a novel therapeutic strategy for vascular injury and remodeling. (C) 2015 Elsevier B.V. All rights reserved.