title: miR-155-dependent regulation of mammalian sterile 20-like kinase 2 (MST2) coordinates inflammation, oxidative stress and proliferation in vascular smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Ming
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Xin-hua
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Ruo-nan
authors.initials: RN
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China.
authors.forename: Xiao-li
authors.initials: XL
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang, China. Electronic address: wjk@hebmu.edu.cn.
authors.forename: Jin-kun
authors.initials: JK
authors.lastname: Wen
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D058426:Neointima / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D000090742:Serine-Threonine Kinase 3; D000099317:Hippo Kinases
chemical_list: D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D000090742:Serine-Threonine Kinase 3; C000715470:MAS1 protein, human; C532623:Mirn155 microRNA, mouse; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases
keywords: Inflammation; MST2; Oxidative stress; Proliferation; VSMC; miR-155