MicroRNA-638 is highly expressed in human vascular smooth muscle cells and inhibits PDGF-BB-induced cell proliferation and migration through targeting orphan nuclear receptor NOR1
MicroRNA-638 is highly expressed in human vascular smooth muscle cells and inhibits PDGF-BB-induced cell proliferation and migration through targeting orphan nuclear receptor NOR1
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MicroRNA-638 在人血管平滑肌细胞中高表达，通过靶向孤儿核受体 NOR1 抑制 PDGF-BB 诱导的细胞增殖和迁移
DOI：
10.1093/cvr/cvt082
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发表时间：
2013-07-01
影响因子：
10.8
通讯作者：
Sun, Jianxin
中科院分区：
文献类型：
--
作者：
Li, Pan;Liu, Yan;Sun, Jianxin
血管平滑肌细胞（VSMC）的异常增殖和迁移是导致动脉粥样硬化和再狭窄等血管病变的重要原因。microRNA是近年来发现的一种重要的细胞调控因子，本研究的目的是寻找与人主动脉平滑肌细胞增殖和迁移有关的新的miRNA调控因子，并利用微阵列技术对血小板源性生长因子（PDGF）刺激后不同时间点的人主动脉平滑肌细胞（SMC）进行分析。在这里，我们确定microRNA-638（miR-638）作为一种转录本，是PDGF刺激后人VSMC中最显著下调的转录本之一。此外，我们通过定量RTPCR证实，miR-638在人VSMC中高度表达，并且其表达在PDGF处理后以剂量和时间依赖性方式显著下调。与SMC增殖中的关键作用一致，我们发现miR-638表达在分化培养基中培养的人VSMC中显著上调，这是一种抑制SMC增殖的条件。此外，我们鉴定了孤儿核受体NOR 1作为miR-638的下游靶基因产物，并且NOR 1的下调对于miR-638介导的对PDGF诱导的细胞周期蛋白D1表达、细胞增殖这些结果表明，miR-638是通过靶向NOR 1/NOR 2调节人VSMC增殖和迁移的关键分子。细胞周期蛋白D通路的研究表明，miR-638在人VSMC中的特异性调节可能代表了一种有吸引力的治疗增殖性血管疾病的方法。
Aberrant vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to the development of vascular pathologies, such as atherosclerosis and restenosis. MicroRNAs have recently emerged as critical modulators in cellular processes and the purpose of this study is to identify novel miRNA regulators implicated in human aortic VSMC proliferation and migration.To identify miRNAs that are differentially expressed in human VSMCs, we performed miRNA microarray analysis in human aortic smooth muscle cells (SMCs) at different time points after platelet-derived growth factor (PDGF) stimulation. Here, we identified microRNA-638 (miR-638) as a transcript that was one of the most significantly down-regulated in human VSMCs after PDGF stimulation. Furthermore, we confirmed, by Quantitative RTPCR, that miR-638 is highly expressed in human VSMCs, and its expression is markedly down-regulated in a dose- and time-dependent manner upon PDGF treatment. Consistent with a critical role in SMC proliferation, we found that miR-638 expression was significantly up-regulated in human VSMCs cultured in differentiation medium, a condition that inhibits SMC proliferation. Furthermore, we identified the orphan nuclear receptor NOR1 as a downstream target gene product of miR-638 and down-regulation of NOR1 is critical for miR-638-mediated inhibitory effects on PDGF-induced cyclin D1 expression, cell proliferation, and migration in human aortic SMCs.These results indicate that miR-638 is a key molecule in regulating human VSMC proliferation and migration by targeting the NOR1/cyclin D pathway and suggest that specific modulation of miR-638 in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.