LncRNA HOXA-AS2 represses endothelium inflammation by regulating the activity of NF-κB signaling

• Published in: Atherosclerosis 2019-02, Vol.281, p.38-46
• Main Authors: Zhu, Xinxing, Liu, Yanli, Yu, Jinjin, Du, Jiang, Guo, Rui, Feng, Yanyan, Zhong, Genshen, Jiang, Yizhou, Lin, Juntang
• Format: Article
• Language: English
• Subjects: Acetylation; Carotid Artery Diseases - genetics; Carotid Artery Diseases - metabolism; Carotid Artery Diseases - pathology; Case-Control Studies; Cell Cycle Proteins - metabolism; Coculture Techniques; Endothelium inflammation; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; HOXA-AS2; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; Inflammation Mediators - metabolism; Negative feedback; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - metabolism; NF-κB; Positive Transcriptional Elongation Factor B - metabolism; Protein Processing, Post-Translational; Proteolysis; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Signal Transduction; THP-1 Cells; Transcription Factor RelA - metabolism; Transcription Factors - metabolism; Transendothelial and Transepithelial Migration
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2018.12.012

Endothelium inflammation, which can lead to endothelial activation and dysfunction, is widely accepted as the major event in multiple vascular disorders. The lncRNA HOXA-AS2 was previously reported to be involved in multiple inflammation-linked cancers. However, the role of HOXA-AS2 in endothelium inflammation is poorly understood. This study aims to determine the regulatory role of HOXA-AS2 in endothelium inflammation and related vascular diseases. High throughput mRNA sequencing was performed to establish expression profiles after HOXA-AS2 depletion. We extracted total RNAs of human peripheral blood mononuclear cells from normal control group and experimental group with carotid artery atherosclerosis, and performed qRT-PCR to assay the correlation between HOXA-AS2 expression and inflammatory vascular diseases. Inhibition of HOXA-AS2 can induce the activation of NF-κB signaling and subsequent inflammatory response. More importantly, HOXA-AS2 is inversely found to be inversely regulated by NF-κB in a negative feedback manner by helping recruit BRD4/P-TEFb complex to HOXA-AS2 promoter region, therefore facilitating release of the promoter-proximal paused RNA polymerase II and activating transcription elongation. We identify HOXA-AS2 as a critical repressor of endothelium inflammation. Moreover, this study offers us a new way to balance the NF-κB signaling-driven excessive endothelium inflammation by establishing a NF-κB/HOXA-AS2 negative feedback loop. Based on these findings, we conclude that HOXA-AS2 may serve as a crucial therapeutic target for various vascular disorders which are significantly associated with endothelium inflammation. [Display omitted] •We identify lncRNA HOXA-AS2 as a critical repressor of endothelium inflammation.•HOXA-AS2 has a significant correlation with carotid artery atherosclerosis.•HOXA-AS2 represses the activation of NF-κB signaling by controlling IκBα degradation and RelA acetylation at K310 site.•NF-κB inversely activates the transcription elongation of HOXA-AS2 by establishing a NF-κB/HOXA-AS2 negative feedback loop.