MicroRNA-663 Regulates Human Vascular Smooth Muscle Cell Phenotypic Switch and Vascular Neointimal Formation

作者：Pan Li, Ni Zhu, Bin Yi, Nadan Wang, Ming Chen, Xiaohua You, Xianxian Zhao, Charalambos Solomides, Yongwen Qin, Jianxin Sun · 发表于：Circulation Research · 年份：2013 · DOI：10.1161/circresaha.113.301306 · 被引用次数：201 · 研究领域：MicroRNA in disease regulation、Angiogenesis and VEGF in Cancer、Nuclear Receptors and Signaling

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 22α, smooth muscle α-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 ...