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Lookup NU author(s): Professor Konstantinos StellosORCiD,
Dr Aikaterini GatsiouORCiD
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© 2016 Nature America, Inc. All rights reserved. Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3′ untranslated region (3′ UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx + regions, which form a long stem-loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3′ UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory-γ 3 and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases.
Author(s): Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, John D, Lunella FF, Jae N, Rossbach O, Amrhein C, Sigala F, Boon RA, Furtig B, Manavski Y, You X, Uchida S, Keller T, Boeckel J-N, Franco-Cereceda A, Maegdefessel L, Chen W, Schwalbe H, Bindereif A, Eriksson P, Hedin U, Zeiher AM, Dimmeler S
Publication type: Article
Publication status: Published
Journal: Nature Medicine
Online publication date: 05/09/2016
Acceptance date: 20/07/2016
ISSN (print): 1078-8956
ISSN (electronic): 1546-170X
Publisher: Nature Publishing Group
PubMed id: 27595325
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