title: The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis.
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.
authors.affiliation: 1] Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA [2] Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA [3].
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: 1] Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA [2] Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA [3].
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: 1] Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA [2] Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Wakako
authors.initials: W
authors.lastname: Takabe
authors.affiliation: 1] Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA [2] Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA [3] Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Ni
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Alberts-Grill
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA.
authors.forename: In-Hwan
authors.initials: IH
authors.lastname: Jang
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, South Korea.
authors.forename: Sangok
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, South Korea.
authors.forename: Wankyu
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, South Korea.
authors.forename: Sang
authors.initials: S
authors.lastname: Won Kang
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, California 95616, USA.
authors.forename: Jai
authors.initials: J
authors.lastname: Woong Seo
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, California 95616, USA.
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
authors.affiliation: 1] Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, USA [2] Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA [3] Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism; D004195:Disease Models, Animal; D004727:Endothelium / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010539:Permeability; D012335:RNA, Ribosomal / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors
chemical_list: D001057:Apolipoproteins E; C000589250:MIRN712 microRNA, human; C000589251:MIRN712 microRNA, mouse; D035683:MicroRNAs; D012335:RNA, Ribosomal; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3