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139 Microrna-214 is a novel player in inflammatory smooth muscle cell differentiation and angioplasty restenosis
  1. Qingzhong Xiao1,
  2. Shiping He2
  1. 1WHRI, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London
  2. 2WHRI, Barts and The London School of Medicine and Dentistry, Queen Mary University of London

Abstract

Background/objective Inflammatory smooth muscle cell (iSMC) differentiation from residential vascular stem/progenitor cells (VSPCs) has been recently recognised as a critical determinant in cardiovascular diseases. We have recently reported an important role for microRNA-214 (miR-214) in mature vascular SMC functions and injury-induced neointima formation. However, little is known about the functional involvements of miR-214 in iSMC differentiation from VSPCs and its contribution to adverse arterial remodelling. In the current study, we aimed to study the functional importance of miR-214 and its target genes in iSMC differentiation and neointima SMC hyperplasia.

Methods and results miR-214 expression was significantly increased during SMC differentiation from VSPCs in response to TGF-β. miR-214 gain/loss-of-function assays showed that miR-214 plays an important role in SMC differentiation from VSPCs. By co-incubating VSPCs with TGF-β and TNFα, VSPCs were induced to differentiate toward iSMCs as evident by a decreased expression level of SMC-specific genes, but an increased level of inflammatory genes in iSMCs. Importantly, such phenotype could be inhibited/rescued by miR-214 over-expression. Both Suppressor of Fused (SuFu) and SMYD Family Member 5 (SMYD5, belongs to the class V-like SAM-binding methyltransferase superfamily) have been predicted as two of the top targets of miR-214 by several computational miRNA target prediction tools, and were indeed negatively regulated by miR-214 during iSMC differentiation. Luciferase assays showed miR-214 substantially repressed wild type, but not the miR-214 binding site mutated version of SuFu and SMYD5 (3’-UTR) gene reporter activity during iSMC differentiation, confirming both SuFu and SMYD5 are the functional targets of miR-214. Data from co-transfection experiments also revealed that inhibition of either SuFu or SMYD5 is required for the inhibitory effect of miR-214 on iSMC differentiation. Further mechanistic studies revealed that increased amount of the Glioma-Associated Oncogene Homolog 1 (GLI1) proteins were translocalized into nuclei in miR-214 over-expressing or SuFu knockdown cells, and the consensus sequence (GACCACCCA) of GLI1 within gene promoters of smooth muscle alpha-actin (SMαA) and serum response factor (SRF) was required for their regulation by miR-214 and SuFu. Importantly, locally enforced expression of miR-214 in the injured vessels significantly reduced SuFu and SMYD5 expression levels, inhibited iSMC number, and prevented neointima SMC hyperplasia after injury.

Conclusions/implications We have reported a novel role for miR-214 in iSMC differentiation from VSPCs and controlling neointima hyperplasia. Our findings provide new insights into the therapeutic effect of miR-214 in vascular diseases.

  • Vascular stem/progenitor cells
  • Inflammatory smooth muscle cell
  • microRNAs

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