MicroRNA-663 regulates human vascular smooth muscle cell phenotypic switch and vascular neointimal formation.
MicroRNA-663 regulates human vascular smooth muscle cell phenotypic switch and vascular neointimal formation.
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MicroRNA-663 调节人血管平滑肌细胞表型转换和血管新内膜形成
DOI：
10.1161/circresaha.113.301306
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发表时间：
2013-10-25
影响因子：
20.1
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Li P;Zhu N;Yi B;Wang N;Chen M;You X;Zhao X;Solomides CC;Qin Y;Sun J
基本原理：血管平滑肌细胞（VSMC）表型转换异常是动脉粥样硬化和血管成形术后再狭窄等血管疾病的标志。microRNAs（miRNAs）已成为VSMC功能的重要调节因子，我们最近发现miR-663对控制人主动脉平滑肌细胞增殖至关重要。目的：探讨miR-663在人血管平滑肌细胞（VSMC）表型转换及新生内膜形成中的作用。方法和结果：通过使用定量逆转录聚合酶链反应，我们发现miR-663在血小板衍生生长因子处理的人主动脉VSMC中显著下调，而在VSMC分化过程中表达显著增加。此外，我们证明miR-663的过表达增加了VSMC分化标记基因的表达，如平滑肌22、平滑肌肌动蛋白、钙调蛋白和平滑肌肌球蛋白重链，并有效地抑制血小板衍生生长因子诱导的VSMC增殖和迁移。我们确定了转录因子JunB和肌球蛋白轻链9作为miR-663在人VSMC中的下游靶点，因为miR-663的过表达显著抑制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。最后，我们发现，在小鼠颈动脉结扎诱导的血管损伤后，adeno-miR-663显著抑制新生内膜病变形成约50%，特别是通过降低JunB表达。结论：这些结果表明，miR-663是通过靶向JunB/肌球蛋白轻链9表达的人VSMC表型转换的新型调节剂。这些发现表明，靶向人VSMC中的miR-663或其特异性下游靶点可能是治疗增殖性血管疾病的一种有吸引力的方法。
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&agr;, smooth muscle &agr;-actin, calponin, and smooth muscle myosin heavy chain, and potently inhibited platelet-derived 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.