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-alpha,
while silencing of NEAT1 profoundly attenuated the TNF-alpha-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-alpha-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