期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 160, 期 -, 页码 111-120出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2021.07.005
关键词
NEAT1; ADAR1; Alu; A-to-I RNA editing; lncRNA; RNA stability; AUF1; Atherosclerosis
资金
- European Research Council (ERC) under the European Union`s Horizon 2020 research and innovation programme (MODVASC) [759248]
- German Research Foundation DFG [SFB834 B12, 75732319]
NEAT1 lncRNA expression is increased in atherosclerosis-related diseases, and may be controlled through ADAR1-catalyzed A-to-I RNA editing to regulate its stability.
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.
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