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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 Article has an altmetric score of 6

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

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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 3

NEXN-AS1 interacts with BAZ1A, which downregulates NEXN expression.

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NEXN-AS1 interacts with BAZ1A, which downregulates NEXN expression.
(A)...
(A) Cultured human vascular endothelial cells were subjected to RNA immunoprecipitation using an anti-BAZ1A antibody, followed by quantitative RT-PCR analysis of NEXN-AS1. The graph shows fold differences in the amount of NEXN-AS1 (or the housekeeping gene GAPDH) in the immunoprecipitate captured by the anti-BAZ1A antibody versus the amount of NEXN-AS1 (or the housekeeping gene GAPDH) in the immunoprecipitate captured by an IgG isotope. Columns and error bars represent mean and SD values, respectively, in 5 samples. *P < 0.05, t test. (B) Cultured vascular endothelial cell lysates were subjected to protein pulldown using either RNA probes corresponding to the full-length NEXN-AS1 (nucleotides 1–2292), the 5′ portion of NEXN-AS1 (nucleotides 1–1000), and the 3′ portion of NEXN-AS1 (nucleotides 1001–2292), respectively, or a control RNA probe for the housekeeping gene GAPDH, followed by immunoblotting analysis using an anti-BAZ1A antibody. (C) Cultured human vascular endothelial cells were transfected with either an NEXN-AS1–expressing lentivirus (LV-NEXN-AS1) or the lentivirus vector (LV vector) as a control, followed by immunofluorescence microscopy. BAZ1A was stained red with a fluorescence-labeled anti-BAZ1A antibody, and the nucleus was stained blue with DAPI. Scale bars: 10 μm. (D) Cultured human vascular endothelial cells were subjected to ChIP using the anti-BAZ1A antibody, followed by quantitative PCR analysis using primers annealing to the NEXN 5′ flanking sequence (Supplemental Figure 3) and the housekeeping gene GAPDH as a reference. Graph shows mean and SD values in 5 samples. *P < 0.05, t test. (E) Cultured human vascular endothelial cells were transfected with either an NEXN-AS1–expressing lentivirus (LV-NEXN-AS1) or the lentivirus vector (LV vector) to serve as a control or with either a BAZ1A siRNA or a scramble (control) siRNA, followed by immunoblotting analysis using an anti-NEXN antibody and an antibody against the housekeeping protein β-actin as a loading control. The graph shows fold difference in mean ( ± SD) NEXN band intensity after standardization against the band intensity of the housekeeping protein β-actin in 5 independent experiments. *P < 0.05, ANOVA with post hoc analysis and Bonferroni’s correction. (F) Cultured human vascular endothelial cells transfected with either a BAZ1A siRNA or a scramble (control) siRNA were subjected to FAIRE, followed by quantitative PCR analysis using primers complementary to the NEXN gene 5′ flanking sequence (Supplemental Figure 3). The graph shows mean and SD values from 5 experiments. *P < 0.05, t test.

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