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EMBO Mol Med. 2013 Jul;5(7):949-66. doi: 10.1002/emmm.201202318. Epub 2013 Jun 3.

MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways.

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  • 1Toronto General Research Institute, University Health Network, Toronto, Canada.

Abstract

Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR-146a and miR-146b are induced in endothelial cells upon exposure to pro-inflammatory cytokines. Despite the rapid transcriptional induction of the miR-146a/b loci, which is in part mediated by EGR-3, miR-146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression. We demonstrate that miR-146 negatively regulates inflammation. Over-expression of miR-146a blunts endothelial activation, while knock-down of miR-146a/b in vitro or deletion of miR-146a in mice has the opposite effect. MiR-146 represses the pro-inflammatory NF-κB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR-146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro-inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases.

© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

KEYWORDS:

atherosclerosis; endothelium; gene regulation; inflammation; microRNA

PMID:
23733368
[PubMed - indexed for MEDLINE]
PMCID:
PMC3721471
Free PMC Article
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