期刊
EMBO MOLECULAR MEDICINE
卷 5, 期 7, 页码 1017-1034出版社
WILEY
DOI: 10.1002/emmm.201202318
关键词
atherosclerosis; endothelium; gene regulation; inflammation; microRNA
资金
- Heart and Stroke Foundation of Ontario [NA 7282]
- Canadian Institutes of Health Research [OCN-126570]
- Heart and Stroke Foundation of Ontario
- Canadian Institutes of Health Research
- Hospital for Sick Children Research Institute
- Heart and Stroke Foundation of Canada
- Ontario Ministry of Economic Development and Innovation
- Canadian Foundation for Innovation
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-kappa B 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.
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