MicroRNA-663 Regulates Human Vascular Smooth Muscle Cell Phenotypic Switch and Vascular Neointimal Formation
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 to be 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 real-time PCR (qRT-PCR), we found that miR-663 was significantly downregulated in human aortic VSMCs upon platelet-derived growth factor (PDGF) 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 SM22α, SM α-actin, calponin, and SM myosin heavy chain, and potently inhibited PDGF induced VSMC proliferation and migration. We identified the transcription factor JunB and myosin light chain 9 (Myl9) as downstream targets of miR-663 in human VSMCs, as overexpression of miR-663 markedly inhibited expression of JunB and its downstream molecules, such as Myl9 and matrix metallopeptidase-9 (MMP-9). Finally, we showed that adeno-miR-663 markedly suppressed the neointimal lesion formation by approximately 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/Myl9 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.
- Received March 4, 2013.
- Revision received August 27, 2013.
- Accepted September 6, 2013.