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首页> 外文期刊>Circulation research: a journal of the American Heart Association >MicroRNA-663 regulates human vascular smooth muscle cell phenotypic switch and vascular neointimal formation
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MicroRNA-663 regulates human vascular smooth muscle cell phenotypic switch and vascular neointimal formation

机译：MicroRNA-663调节人血管平滑肌细胞表型转换和血管新内膜形成

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Rationale: Abnormal phenotypic switch of vascular smooth muscle cell (VSMC) is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. MicroRNAs (miRNAs) have emerged as important regulators for VSMC function, and we recently identified miR-663 as critical for controlling human aortic smooth muscle cell proliferation. Objective: To investigate whether miR-663 plays a role in human VSMC phenotypic switch and the development of neointima formation. Methods and Results: By using quantitative reverse-transcription polymerase chain reaction, we found that miR-663 was significantly downregulated in human aortic VSMCs on platelet-derived growth factor treatment, whereas expression was markedly increased during VSMC differentiation. Furthermore, we demonstrated that overexpression of miR-663 increased expression of VSMC differentiation marker genes, such as smooth muscle 22?, smooth muscle ?-actin, calponin, and smooth muscle myosin heavy chain, and potently inhibited plateletderived growth factor-induced VSMC proliferation and migration. We identified the transcription factor JunB and myosin light chain 9 as downstream targets of miR-663 in human VSMCs, because overexpression of miR-663 markedly inhibited expression of JunB and its downstream molecules, such as myosin light chain 9 and matrix metalloproteinase 9. Finally, we showed that adeno-miR-663 markedly suppressed the neointimal lesion formation by ?50% in mice after vascular injury induced by carotid artery ligation, specifically via decreased JunB expression. Conclusions: These results indicate that miR-663 is a novel modulator of human VSMC phenotypic switch by targeting JunB/myosin light chain 9 expression. These findings suggest that targeting miR-663 or its specific downstream targets in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases. (Circ Res. 2013;113:1117-1127.).
机译：理由：血管平滑肌细胞（VSMC）的异常表型转换是血管成形术后血管疾病的标志，如动脉粥样硬化和再狭窄。 MicroRNA（miRNA）已成为VSMC功能的重要调节剂，我们最近发现miR-663对控制人主动脉平滑肌细胞的增殖至关重要。目的：探讨miR-663是否在人VSMC表型转换和新内膜形成的发展中起作用。方法和结果：通过定量逆转录聚合酶链反应，我们发现在血小板衍生的生长因子治疗下，人主动脉VSMC中miR-663明显下调，而在VSMC分化过程中表达显着增加。此外，我们证明了miR-663的过表达增加了VSMC分化标志物基因的表达，例如平滑肌22α，平滑肌β-肌动蛋白，钙蛋白和平滑肌肌球蛋白重链，并有效抑制了血小板衍生的生长因子诱导的VSMC增殖。和迁移。我们将转录因子JunB和肌球蛋白轻链9确定为人类VSMC中miR-663的下游靶标，因为miR-663的过表达显着抑制了JunB及其下游分子（如肌球蛋白轻链9和基质金属蛋白酶9）的表达。 ，我们发现，在通过颈动脉结扎引起的血管损伤后，特别是通过降低JunB表达，腺苷miR-663可显着抑制小鼠新内膜病变的形成约50％。结论：这些结果表明，miR-663通过靶向JunB /肌球蛋白轻链9表达，是人VSMC表型转换的新型调节剂。这些发现表明，在人VSMC中靶向miR-663或其特定的下游靶标可能代表了一种治疗增生性血管疾病的有吸引力的方法。 （Circ Res.2013; 113：1117-1127。）。

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