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

Dong Ju Son, Sandeep Kumar, Wakako Takabe, Chan Woo Kim, Chih-Wen Ni, Noah Alberts-Grill, In-Hwan Jang, Sangok Kim, Wankyu Kim, Sang Won Kang, Andrew H. Baker, Jai Woong Seo, Katherine W. Ferrara and Hanjoong Jo ()
Additional contact information
Dong Ju Son: Georgia Institute of Technology and Emory University
Sandeep Kumar: Georgia Institute of Technology and Emory University
Wakako Takabe: Georgia Institute of Technology and Emory University
Chan Woo Kim: Georgia Institute of Technology and Emory University
Chih-Wen Ni: Georgia Institute of Technology and Emory University
Noah Alberts-Grill: Emory University
In-Hwan Jang: Georgia Institute of Technology and Emory University
Sangok Kim: Ewha Womans University
Wankyu Kim: Ewha Womans University
Sang Won Kang: Ewha Womans University
Andrew H. Baker: Institute of Cardiovascular and Medical Sciences, University of Glasgow
Jai Woong Seo: University of California
Katherine W. Ferrara: University of California
Hanjoong Jo: Georgia Institute of Technology and Emory University

Nature Communications, 2013, vol. 4, issue 1, 1-15

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms4000

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