Journal
NATURE MEDICINE
Volume 22, Issue 10, Pages 1140-1150Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4172
Keywords
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Funding
- 'FFF-Innovation' program of the J.W. Goethe University Frankfurt
- August-Scheidel Stiftung
- Excellence Cluster Cardio-Pulmonary System (ECCPS)
- Else Kroner-Fresenius-Stiftung
- LOEWE Center for Cell and Gene Therapy (State of Hessen)
- German Center for Cardiovascular Research (DZHK)
- German Cardiac Society
- DFG [SFB902]
- Swedish Heart and Lung Foundation
- Karolinska Institutet
- Stockholm County Council
- Foundation for Strategic Research
- European Commission
- Swedish Society for Medical Research (SSMF)
- Swedish Research Council
- Swedish Heart-Lung Foundation
- LOEWE program 'Medical RNomics' (State of Hessen)
- Uppdrag Besegra Stroke
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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 cytokines interferon-gamma and tumor-necrosis-factor-alpha 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.
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