Yang Zhan, Zheng Bin, Zhang Yu, He Ming, Zhang Xin-hua, Ma Dong, Zhang Ruo-nan, Wu Xiao-li, Wen Jin-kun
Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
Biochim Biophys Acta. 2015 Jul;1852(7):1477-89. doi: 10.1016/j.bbadis.2015.04.012. Epub 2015 Apr 17.
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 proto-oncogene 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.
针对血管损伤，炎症、氧化应激和细胞增殖通常在血管组织中同时发生。我们之前观察到，参与增殖和炎症的微小RNA-155（miR-155）与内膜增生有关；然而，其调节这些过程的分子机制仍 largely未知。在本研究中，我们观察到，在钢丝损伤的股动脉中，miR-155缺失会减少血管平滑肌细胞（VSMC）增殖和内膜形成，而miR-155增加则会使其增加。在培养的VSMC中也观察到了miR-155的增殖作用。值得注意的是，在miR-155基因敲除小鼠的损伤动脉中，miR-155靶蛋白哺乳动物不育20样激酶2（MST2）的表达增加。miR-155直接抑制MST2，从而通过促进RAF原癌基因丝氨酸/苏氨酸蛋白激酶（Raf-1）与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来激活细胞外信号调节激酶（ERK）途径；这些作用共同导致VSMC增殖和血管重塑。我们的数据表明，MST2通过改变MEK与Raf-1和MST2在血管损伤时的相互作用来介导miR-155促进的炎症和氧化应激反应。因此，抑制内源性miR-155可能是治疗血管损伤和重塑的一种新策略。
