The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis

• Type of Material: Article
• Authors: Dong Ju Son, Georgia Institute of Technology; Sandeep Kumar, Emory University; Wakako Takabe, Georgia Institute of Technology; Chan Woo Kim, Georgia Institute of Technology; Chih-Wen Ni, Georgia Institute of Technology; Noah Alberts-Grill, Emory University; Alberts-Grill In-Hwan, Jang, Georgia Institute of Technology; Sangok Kim, Ewha Womans University; Wankyu Kim, Ewha Womans University; Sang Won Kang, Ewha Womans University; Andrew H. Baker, University of Glasgow; Jai Woong Seo, University of California Davis; Katherine W. Ferrara, University of California Davis; Hanjoong Jo, Emory University
• Language: English
• Date: 2013-12-01
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms4000
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 4
• Start Page: 3000
• End Page: 3000
• Grant/Funding Information: This work was supported by funding from NIH grants HL095070, HL70531and a World Class University Project (R31-2008-000-10010-0) from the Ministry of Science, Technology and Education of S. Korea (MEST) to HJ, HHSN268201000043C to HJ and KF, and by the Global Frontier Project grant (NRF-M1AXA-002-2010-0029763) and the grant (2011-0014992) from MEST to WK. SK is an American Heart Association postdoctoral fellow.
• Keywords: MICE; EXPRESSION; DEFICIENCY; SMOOTH-MUSCLE-CELLS; Multidisciplinary Sciences; IN-VITRO; Science & Technology - Other Topics; TISSUE INHIBITOR; SHEAR-STRESS; MICROPROCESSOR COMPLEX; DISTURBED FLOW; LAMINAR-FLOW; Science & Technology
• Research Categories: Engineering, Biomedical; Health Sciences, General

Abstract

MicroRNAs (miRNAs) regulate cardiovascular biology and disease, but the role of flow-sensitive microRNAs in atherosclerosis is still unclear. Here we identify miRNA-712 (miR-712) as a mechanosensitive miRNA upregulated by disturbed flow (d-flow) in endothelial cells, in vitro and in vivo. We also show that miR-712 is derived from an unexpected source, pre-ribosomal RNA, in an exoribonuclease-dependent but DiGeorge syndrome critical region 8 (DGCR8)-independent manner, suggesting that it is an atypical miRNA. Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase 3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) and stimulate pro-atherogenic responses, endothelial inflammation and permeability. Furthermore, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis. Finally, we report that human miR-205 shares the same 'seed sequence' as murine-specific miR-712 and also targets TIMP3 in a flow-dependent manner. Targeting these mechanosensitive 'athero-miRs' may provide a new treatment paradigm in atherosclerosis.