Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease.
J Mol Cell Cardiol
; 160: 111-120, 2021 11.
Article
in En
| MEDLINE
| ID: mdl-34302813
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Coronary Artery Disease
/
Signal Transduction
/
Adenosine
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RNA Editing
/
Alu Elements
/
RNA Stability
/
Atherosclerosis
/
Plaque, Atherosclerotic
/
RNA, Long Noncoding
/
Inosine
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Risk_factors_studies
Limits:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
J Mol Cell Cardiol
Year:
2021
Document type:
Article
Affiliation country: