OCT4 regulated neointimal formation in injured mouse arteries by matrix metalloproteinase 2-mediated smooth muscle cells proliferation and migration
OCT4 regulated neointimal formation in injured mouse arteries by matrix metalloproteinase 2-mediated smooth muscle cells proliferation and migration
复制标题
OCT4 通过基质金属蛋白酶 2 介导的平滑肌细胞增殖和迁移来调节受损小鼠动脉中的新内膜形成。
DOI：
10.1002/jcp.30248
复制
发表时间：
2020-12-28
影响因子：
5.6
通讯作者：
Qin, Yongwen
中科院分区：
文献类型：
--
作者：
Ding, Xueyan;Yan, Yan;Qin, Yongwen
血管平滑肌细胞（vascular smooth muscle cells，VSMCs）的过度增殖和迁移在新生内膜增生和血管再狭窄中起重要作用。本研究旨在探讨八聚体结合转录因子4（octamer-binding transcription factor 4，OCT 4）在血管损伤后新生内膜形成中的作用及其机制。定量逆转录聚合酶链反应和蛋白质印迹结果显示，OCT 4水平在损伤的颈动脉显着增加。免疫组织化学和免疫荧光检测证实，OCT 4的表达增加主要定位于新生内膜的α-SMA阳性VSMCs，并与PCNA共定位于VSMCs的核中。腺病毒介导的OCT 4过表达在损伤的颈动脉中加剧内膜增厚，而OCT 4敲低显著抑制内膜增厚。体外实验证实，血小板源性生长因子-BB（PDGF-BB）可诱导VMSC中OCT 4表达增加，并呈时间依赖性。OCT 4的过表达显著促进VSMCs的增殖和迁移，而OCT 4的敲低则显著抑制PDGF-BB诱导的VSMCs的过度增殖和迁移。生物信息学分析、双荧光素酶报告基因分析和染色质免疫沉淀分析证实OCT 4可通过促进基质金属蛋白酶2（MMP 2）的转录而上调MMP 2的表达。此外，MMP 2的敲低显著减弱OCT 4介导的VSMCs增殖和迁移。这些结果表明，OCT 4通过MMP 2介导的VSMCs增殖和迁移促进血管损伤后的新生内膜形成，靶向VSMCs中的OCT 4可能是血管再狭窄的新治疗策略。
The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) play vital roles in neointimal hyperplasia and vascular restenosis. In the present study, we aimed to investigate the function and mechanism of octamer-binding transcription factor 4 (OCT4, a key transcription factor for maintaining stem cells in de-differentiated state) on neointima formation in response to vascular injury. Quantitative reverse-transcription polymerase chain reaction and western blot results displayed a significant increase of OCT4 levels in injured carotid arteries. Immunohistochemistry and immunofluorescence assays confirmed that the increased OCT4 expression was primarily localized in alpha-SMA-positive VSMCs from neointima, and colocalized with PCNA in the nuclei of VSMCs. Adenovirus-mediated OCT4 overexpression in injured carotid arteries exacerbated intimal thickening, while OCT4 knockdown significantly inhibited intimal thickening. In-vitro experiments confirmed that the increased OCT4 expression in VMSCs could be induced by platelet-derived growth factor-BB (PDGF-BB) in a time-dependent manner. Overexpression of OCT4 greatly promoted VSMCs proliferation and migration, while OCT4 knockdown significantly retarded the PDGF-BB-induced excessive proliferation and migration of VSMCs. Bioinformatics analysis, dual-luciferase reporter assay, and chromatin immunoprecipitation assay confirmed that OCT4 could upregulate matrix metalloproteinases 2 (MMP2) expression through promoting its transcription. Moreover, knockdown of MMP2 significantly attenuated OCT4-mediated VSMCs proliferation and migration. These results indicated that OCT4 facilitated neointimal formation in response to vascular injury by MMP2-mediated VSMCs proliferation and migration, and targeting OCT4 in VSMCs might be a novel therapeutic strategy for vascular restenosis.