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

• 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
• Journal Title: Nature Communications
• Volume: Volume 4
• Publisher: Nature Publishing Group: Nature Communications | 2013-12-01, Pages 3000-3000
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/ncomms4000
• Subjects: Engineering, Biomedical; Health Sciences, General
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; SMOOTH-MUSCLE-CELLS; SHEAR-STRESS; DISTURBED FLOW; IN-VITRO; MICROPROCESSOR COMPLEX; TISSUE INHIBITOR; LAMINAR-FLOW; EXPRESSION; MICE; DEFICIENCY

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.