About this item:

151 Views | 129 Downloads

Author Notes:

Address for Correspondence: Hanjoong Jo, PhD, Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Health Sciences Research Building, E170, Atlanta, Georgia 30322, hanjoong.jo@bme.gatech.edu. Telephone: 404-712-9654, Fax: 404-727-3330

DJS and SK contributed equally to the manuscript. DJS, SK, WT, CN, JWS and KWF designed the experiments. DJS, SK, WT, CN, CW, JWS, SK, IHJ and NAG performed the experiments.

DJS, WT, SK, CN, CWK, SOK, WKK, JWS, and NAG analyzed the data. AHB and KWF provided key reagents. SK, DJS, and HJ wrote the manuscript.

HJ supervised the overall research, secured funding, designed experiments and interpreted results and wrote the manuscript.

We thank Dr. Oskar Laur at the Emory Custom Cloning Core facility for generating TIMP3 mutants.

Subjects:

Research Funding:

This work was supported by funding from NIH grants HL095070, HL70531and a World Class University Project (R31-2008-000-10010-0) from the Ministry of Science, Technology and Education of S. Korea (MEST) to HJ, HHSN268201000043C to HJ and KF, and by the Global Frontier Project grant (NRF-M1AXA-002-2010-0029763) and the grant (2011-0014992) from MEST to WK. SK is an American Heart Association postdoctoral fellow.

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

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

Show all authors Show less authors

Tools:

Journal Title:

Nature Communications

Volume:

Volume 4

Publisher:

, Pages 3000-3000

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2013 Macmillan Publishers Limited. All rights reserved.

Export to EndNote