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

• Published in: Circulation research Vol. 113; no. 10; pp. 1117 - 1127
• Main Authors: Li, Pan, Zhu, Ni, Yi, Bing, Wang, Nadan, Chen, Ming, You, Xiaohua, Zhao, Xianxian, Solomides, Charalambos C, Qin, Yongwen, Sun, Jianxin
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 25.10.2013
• Subjects: Actins - metabolism; Animals; Aorta - cytology; Aorta - drug effects; Aorta - metabolism; Calcium-Binding Proteins - metabolism; Calponins; Carotid Arteries - cytology; Carotid Arteries - drug effects; Carotid Arteries - metabolism; Cell Differentiation - physiology; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Down-Regulation - drug effects; Humans; In Vitro Techniques; Ligation; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins - metabolism; MicroRNAs - physiology; Models, Animal; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myosin Heavy Chains - metabolism; Myosin Light Chains - genetics; Myosin Light Chains - metabolism; Neointima - physiopathology; Phenotype; Platelet-Derived Growth Factor - pharmacology; Transcription Factors - genetics; Transcription Factors - metabolism; miR-663; migration; proliferation; vascular remodeling; vascular smooth muscle cells
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.113.301306

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 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.