Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease

Vlachogiannis, Nikolaos I and Sachse, Marco and Georgiopoulos, Georgios and Zormpas, Eleftherios and Bampatsias, Dimitrios and Delialis, Dimitrios and Bonini, Francesca and Galyfos, George and Sigala, Fragiska and Stamatelopoulos, Kimon and Gatsiou, Aikaterini and Stellos, Konstantinos (2021) Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease. Journal of molecular and cellular cardiology, 160. pp. 111-120. ISSN 0022-2828

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Abstract

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.

Item Type:
Journal Article
Journal or Publication Title:
Journal of molecular and cellular cardiology
Additional Information:
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1312
Subjects:
?? geneticstransfectionmolecular biologycardiology and cardiovascular medicine ??
ID Code:
222124
Deposited By:
Deposited On:
16 Jul 2024 01:24
Refereed?:
Yes
Published?:
Published
Last Modified:
04 Oct 2024 00:28