Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXN
Yan-Wei Hu, … , Nilesh J. Samani, Shu Ye
Yan-Wei Hu, … , Nilesh J. Samani, Shu Ye
Published December 27, 2018
Citation Information: J Clin Invest. 2019;129(3):1115-1128. https://doi.org/10.1172/JCI98230.
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Research Article Vascular biology

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

Abstract

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.

Authors

Yan-Wei Hu, Feng-Xia Guo, Yuan-Jun Xu, Pan Li, Zhi-Feng Lu, David G. McVey, Lei Zheng, Qian Wang, John H. Ye, Chun-Min Kang, Shao-Guo Wu, Jing-Jing Zhao, Xin Ma, Zhen Yang, Fu-Chun Fang, Yu-Rong Qiu, Bang-Ming Xu, Lei Xiao, Qian Wu, Li-Mei Wu, Li Ding, Tom R. Webb, Nilesh J. Samani, Shu Ye

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Figure 6

NEXN deters atherosclerosis in a mouse model.

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NEXN deters atherosclerosis in a mouse model. (A) NEXN+/– ApoE–/– mice a...
(A) NEXN+/– ApoE–/– mice and NEXN+/+ ApoE–/– littermates, 6 weeks of age, were fed a Western high-fat diet for 12 weeks, followed by aorta en face oil red O staining and immunohistochemical analyses of aortic root cross sections. Shown in the figure are representative images of aorta en face oil red O staining and aortic root cross-section staining with H&E, oil red O (for lipids), anti-CD68 antibody (for macrophages), anti-αSMA antibody (for VSMCs), trichrome (for collagens), von Kossa (for calcification), and antibodies against ICAM1, VCAM1, MCP1, TNF-α, IL-6, MMP1, and MMP9, respectively. Scale bars: 300 uM. Graphs show differences (mean ± SD) between the 2 groups in lesion area, cap thickness, and percentages of positive staining areas, respectively. n = 10 animals in each group. *P < 0.05, t test. (B) ApoE–/– mice were injected with an adeno-associated virus to overexpress NEXN or with a negative control adeno-associated virus and fed the Western high-fat diet for 12 weeks, followed by oil red O staining of aortic root cross sections. Figure shows representative images of oil red O staining and mean ± SD percentage of the atherosclerotic lesion area in total lumen area in the 2 groups. Original magnification, ×100 (upper); ×200 (lower). n = 10 animals in each group. *P < 0.05, t test.