MicroRNA-22 Reduces Neointima Formation Via Regulating Smooth Muscle Cell Phenotypic Modulation

Background and Aim:Vascular remodeling plays a important role in the pathogenesis of vascular diseases such as atherosclerosis and post-angioplasty restenosis.Aberrant vascular smooth muscle cell(VSMC)proliferation and migration have been implicated in such abnormal vascular remodelling.microRNA-22(miR-22)has recently been reported to play a regulatory role during vascular smooth muscle cell differentiation from stem cells.However,its importance in mature VSMC functions as well as neointima formation following vascular injury remains to be elucidated.In this study,we aimed to investigate the potential involvement of miR-22 in mature VSMC phenotypic modulation and neointima formation,and unravel its underlying molecular mechanisms.Methods and Results:Expression level of miR-22 was closely modulated during VSMC phenotypic modulation,and in the injured arteries.miR-22 over-expression significantly increased VSMC contractile gene expression and inhibited VSMC proliferation and migration,whilst the opposite effect was observed when endogenous miR-22 was knocked down in VSMCs.As expected miR-22's target gene,methyl-CpG binding protein 2(MECP2),identified in our previous study,exhibits a regulatory role in VSMC phenotypic modulation.A transcriptional regulator and oncoprotein,Ecotropic Virus Integration Site 1 Protein Homolog(EVIL),has been identified as a novel miR-22 target gene in miR-22-mediated VSMC phenotypic modulation.Of note,perivascular enforced expression of miR-22 in the injured vessels significantly reduced the expression levels of MECP2 and EVI1,decreased VSMC proliferation,and inhibited neointima formation in wire-injured femoral arteries.Finally,miR-22 expression was significantly reduced,while MECP2 and EVI1 expression levels were dramatically increased in diseased human arteries;and an inverse relationship could be observed between miR-22 and MECP2 and/or EVI1 in human femoral arteries with or without atherosclerotic lesions.Conclusion:Our data presented in the current study reveal that miR-22 is a novel regulator of VSMC phenotype switching and vascular neointimal lesion formation via its target genes,MECP2 and EVI1.These findings may have extensive implications for the treatment of a variety of proliferative vascular diseases.