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Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXN.

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journal contribution
posted on 04.03.2019, 09:52 by Y-W Hu, F-X Guo, Y-J Xu, P Li, Z-F Lu, DG McVey, L Zheng, Q Wang, JH Ye, C-M Kang, S-G Wu, J-J Zhao, X Ma, Z Yang, F-C Fang, Y-R Qiu, B-M Xu, L Xiao, Q Wu, L-M Wu, L Ding, TR Webb, NJ Samani, Shu Ye
Noncoding RNAs are emerging as important players in gene regulation and disease pathogeneses. Here, we show that a previously uncharacterized long noncoding RNA, nexilin F-actin binding protein antisense RNA 1 (NEXN-AS1), modulates the expression of the actin-binding protein NEXN and that NEXN exerts a protective role against atherosclerosis. An expression microarray analysis showed that the expression of both NEXN-AS1 and NEXN was reduced in human atherosclerotic plaques. In vitro experiments revealed that NEXN-AS1 interacted with the chromatin remodeler BAZ1A and the 5' flanking region of the NEXN gene and that it also upregulated NEXN expression. Augmentation of NEXN-AS1 expression inhibited TLR4 oligomerization and NF-κB activity, downregulated the expression of adhesion molecules and inflammatory cytokines by endothelial cells, and suppressed monocyte adhesion to endothelial cells. These inhibitory effects of NEXN-AS1 were abolished by knockdown of NEXN. In vivo experiments using ApoE-knockout mice fed a Western high-fat diet demonstrated that NEXN deficiency promoted atherosclerosis and increased macrophage abundance in atherosclerotic lesions, with heightened expression of adhesion molecules and inflammatory cytokines, whereas augmented NEXN expression deterred atherosclerosis. Patients with coronary artery disease were found to have lower blood NEXN levels than healthy individuals. These results indicate that NEXN-AS1 and NEXN represent potential therapeutic targets in atherosclerosis-related diseases.

Funding

This work was supported by the National Natural Sciences Foundation of China (grant nos. 81871701, 81572051, 81500387, and 81370202), the Natural Science Fund of Guangdong (grant nos. 2017A030313535 and 2018A030313533), the Science and Technology Program of Guangzhou (grant nos. 201607010267 and 201707010156), and the British Heart Foundation (grant nos. RG/16/13/32609 and PG/16/9/31995). This work falls under the portfolio of research conducted within the NIHR Leicester Biomedical Research Centre.

History

Citation

Journal of Clinical Investigation, 2019, 129(3):1115–1128

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Journal of Clinical Investigation

Publisher

American Society for Clinical Investigation

eissn

1558-8238

Acceptance date

18/12/2018

Copyright date

2018

Available date

04/03/2019

Publisher version

https://www.jci.org/articles/view/98230

Language

en

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