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

Author

Listed:
  • Dong Ju Son

    (Georgia Institute of Technology and Emory University
    Emory University)

  • Sandeep Kumar

    (Georgia Institute of Technology and Emory University
    Emory University)

  • Wakako Takabe

    (Georgia Institute of Technology and Emory University
    Emory University)

  • Chan Woo Kim

    (Georgia Institute of Technology and Emory University
    Emory University
    Ewha Womans 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
    Emory University
    Ewha Womans University)

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.

Suggested Citation

  • 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. , 2013. "The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis," Nature Communications, Nature, vol. 4(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms4000
    DOI: 10.1038/ncomms4000
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    Cited by:

    1. Christoph Schürmann & Felix Gremse & Hanjoong Jo & Fabian Kiessling & Ralf P Brandes, 2015. "Micro-CT Technique Is Well Suited for Documentation of Remodeling Processes in Murine Carotid Arteries," PLOS ONE, Public Library of Science, vol. 10(6), pages 1-11, June.

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