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, Hanjoong Jo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3000
JournalNature Communications
Volume4
DOIs
Publication statusPublished - 2013

Keywords

  • Animals
  • Apolipoproteins E
  • Atherosclerosis
  • Cardiovascular Diseases
  • Disease Models, Animal
  • Endothelium
  • Endothelium, Vascular
  • Gene Silencing
  • Humans
  • Inflammation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs
  • Myocytes, Smooth Muscle
  • Permeability
  • RNA, Ribosomal
  • Tissue Inhibitor of Metalloproteinase-3

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