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 Seo, Katherine W. Ferrara, Hanjoong Jo

Research output: Contribution to journalArticle

119 Citations (Scopus)

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 (US)
Article number3000
JournalNature Communications
Volume4
StatePublished - 2013

Fingerprint

ribonucleic acids
arteriosclerosis
Ribosomal RNA
MicroRNAs
Atherosclerosis
inhibitors
Inflammation
Tissue Inhibitor of Metalloproteinase-3
biology
seeds
permeability
Exoribonucleases
DiGeorge Syndrome
Disintegrins
matrices
Endothelial cells
Metalloproteases
Matrix Metalloproteinases
Seed
Permeability

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Son, D. J., Kumar, S., Takabe, W., Kim, C. W., Ni, C. W., Alberts-Grill, N., ... Jo, H. (2013). The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. Nature Communications, 4, [3000].

The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. / Son, Dong Ju; Kumar, Sandeep; Takabe, Wakako; Kim, Chan Woo; Ni, Chih Wen; Alberts-Grill, Noah; Jang, In Hwan; Kim, Sangok; Kim, Wankyu; Won Kang, Sang; Baker, Andrew H.; Seo, Jai; Ferrara, Katherine W.; Jo, Hanjoong.

In: Nature Communications, Vol. 4, 3000, 2013.

Research output: Contribution to journalArticle

Son, DJ, Kumar, S, Takabe, W, Kim, CW, Ni, CW, Alberts-Grill, N, Jang, IH, Kim, S, Kim, W, Won Kang, S, Baker, AH, Seo, J, Ferrara, KW & Jo, H 2013, 'The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis.', Nature Communications, vol. 4, 3000.
Son, Dong Ju ; Kumar, Sandeep ; Takabe, Wakako ; Kim, Chan Woo ; Ni, Chih Wen ; Alberts-Grill, Noah ; Jang, In Hwan ; Kim, Sangok ; Kim, Wankyu ; Won Kang, Sang ; Baker, Andrew H. ; Seo, Jai ; Ferrara, Katherine W. ; Jo, Hanjoong. / The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. In: Nature Communications. 2013 ; Vol. 4.
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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.",
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