조한중 (이화여자대학교, Emory University and Georgia Institute of Technology) | 한빛사논문 > 한빛사

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이화여자대학교, Emory University and Georgia Institute of Technology

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Nat. Commun., 4, Article number: 3000, Published online:18 December 2013, doi: 10.1038/ncomms4000 The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis

Abstract

Dong Ju Son^1,2,*, Sandeep Kumar^1,2,*, Wakako Takabe^1,2, Chan Woo Kim^1,2,3, Chih-Wen Ni¹,
Noah Alberts-Grill², In-Hwan Jang¹, Sangok Kim⁴, Wankyu Kim⁴, Sang Won Kang⁴, Andrew H. Baker⁵,
Jai Woong Seo⁶, Katherine W. Ferrara⁶ & Hanjoong Jo^1,2,3

¹Wallace 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. ⁴ Department of Life Science, Ewha Womans University, Seoul, South Korea. ⁵ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK. ⁶ Department of Biomedical Engineering, University of California, Davis, California 95616, USA.
^* These authors contributed equally to this work.

Correspondence and requests for materials should be addressed to H.J.

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.

논문정보

형식Research article
게재일2013년 12월 (BRIC 등록일 2013-12-23)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2016-12-28)

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