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Lookup NU author(s): Dr Nikolaos VlachogiannisORCiD, Dr Georgios Georgiopoulos, Lefteris Zormpas, Professor Kimon Stamatelopoulos, Dr Aikaterini GatsiouORCiD, Professor Konstantinos StellosORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2021. Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo‐ double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.
Author(s): Vlachogiannis NI, Sachse M, Georgiopoulos G, Zormpas E, Bampatsias D, Delialis D, Bonini F, Galyfos G, Sigala F, Stamatelopoulos K, Gatsiou A, Stellos K
Publication type: Article
Publication status: Published
Journal: Journal of Molecular and Cellular Cardiology
Year: 2021
Volume: 160
Pages: 111-120
Print publication date: 01/11/2021
Online publication date: 21/07/2021
Acceptance date: 16/01/2021
Date deposited: 17/08/2021
ISSN (print): 0022-2828
ISSN (electronic): 1095-8584
Publisher: Academic Press
URL: https://doi.org/10.1016/j.yjmcc.2021.07.005
DOI: 10.1016/j.yjmcc.2021.07.005
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