CEMIP regulates the proliferation and migration of vascular smooth muscle cells in atherosclerosis through the WNT-beta-catenin signaling pathway
CEMIP regulates the proliferation and migration of vascular smooth muscle cells in atherosclerosis through the WNT-beta-catenin signaling pathway
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DOI：
10.1139/bcb-2019-0249
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发表时间：
2020-04-01
影响因子：
2.9
通讯作者：
Tian, Wei
中科院分区：
文献类型：
--
作者：
Xue, Qiang;Wang, Xiaoli;Tian, Wei
在这项研究中，我们研究了细胞迁移诱导和透明质酸结合蛋白（CEMIP）在血管平滑肌细胞（VSMCs）的增殖和迁移的调节作用。与健康受试者和未经治疗的VSMCs的血浆相比，动脉粥样硬化患者的血浆样本和血小板衍生生长因子-BB（PDGF-BB）刺激的VSMCs中CEMIP的mRNA和蛋白水平上调。沉默CEMIP可抑制VSMC中PDGF-BB诱导的细胞迁移和增殖，这一点使用细胞计数试剂盒-8测定、5-乙炔基-2 '-脱氧尿苷（EDU）测定、流式细胞术、伤口愈合测定和Transwell测定来确定。CEMIP的过表达通过激活Wnt-β-catenin信号通路和上调其靶基因（包括基质金属蛋白酶-2、基质金属蛋白酶-7、细胞周期蛋白D1和c-myc）促进VSMCs的增殖和迁移，而CEMIP缺乏则表现出相反的作用。通过静脉注射表达si-CEMIP的慢病毒载体敲低ApoE（-/-）小鼠中的CEMIP可保护其免受高脂饮食诱导的动脉粥样硬化，如与正常表达CEMIP的小鼠相比减少的主动脉病变面积、主动脉窦病变面积和血脂浓度所示。这些结果表明，CEMIP通过激活WNT-β-catenin信号通路调节动脉粥样硬化中VSMCs的增殖和迁移，这表明CEMIP用于动脉粥样硬化管理的治疗潜力。
In this study we investigated the regulatory role of cell-migration-inducing and hyaluronan-binding protein (CEMIP) in the proliferation and migration of vascular smooth muscle cells (VSMCs). The mRNA and protein levels of CEMIP were upregulated in the plasma samples from patients with atherosclerosis, and in VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB), compared with plasma from healthy subjects and untreated VSMCs. Silencing CEMIP suppressed PDGF-BB-induced cell migration and proliferation in VSMCs, as determined using a Cell Counting Kit-8 assays, 5-ethynyl-2'-deocyuridine (EDU) assays, flow cytometry, wound healing assays, and Transwell assays. Overexpression of CEMIP promoted the proliferation and migration of VSMCs via activation of the Wnt-beta-catenin signaling pathway and the upregulation of its target genes, including matrix metalloproteinase-2, matrix metalloproteinase-7, cyclin D1, and c-myc, whereas CEMIP deficiency showed the opposite effects. The knockdown of CEMIP in ApoE(-/-) mice by intravenous injection of lentiviral vector expressing si-CEMIP protected against high-fat-diet-induced atherosclerosis, as shown by the reduced aortic lesion areas, aortic sinus lesion areas, and the concentration of blood lipids compared with mice normally expressing CEMIP. These results demonstrated that CEMIP regulates the proliferation and migration of VSMCs in atherosclerosis by activating the WNT-beta-catenin signaling pathway, which suggests the therapeutic potential of CEMIP for the management of atherosclerosis.