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

Citation:

Son DJ, Kumar S, Takabe W, Kim CW, Ni CW, Alberts-Grill N, Jang IH, Kim S, Kim W, Won Kang S, Baker AH, Woong Seo J, Ferrara KW, Jo H. The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. Nat Commun 2013;4:3000.

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.

Notes:

Son, Dong JuKumar, SandeepTakabe, WakakoKim, Chan WooNi, Chih-WenAlberts-Grill, NoahJang, In-HwanKim, SangokKim, WankyuWon Kang, SangBaker, Andrew HWoong Seo, JaiFerrara, Katherine WJo, HanjoongengHHSN268201000043C/HL/NHLBI NIH HHS/HHSN268201000043C/PHS HHS/HL095070/HL/NHLBI NIH HHS/HL113451/HL/NHLBI NIH HHS/HL70531/HL/NHLBI NIH HHS/P01 HL095070/HL/NHLBI NIH HHS/P20 HL113451/HL/NHLBI NIH HHS/R01 HL119798/HL/NHLBI NIH HHS/T32 AI007610/AI/NIAID NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tEngland2013/12/19 06:00Nat Commun. 2013;4:3000. doi: 10.1038/ncomms4000.