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

Hu, Yan‐Wei; Guo, Feng; Xu, Yuzhong; Li, Pan; Lu, Zhifeng; McVey, David G.; Zheng, Lei; Wang, Qian; Ye, John H.; Kang, Chun‐Min; Wu, Shao-Guo; Zhao, Jingjing; Ma, Xin; Yang, Zhen; Fang, Fuchun; Qiu, Yurong; Xu, Bang-Ming; Xiao, Lei; Qian, Wei; Wu, Limei; Li, Ding; Webb, Tom R.; Samani, Nilesh J.; Ye, Shu

doi:10.1172/jci98230

Cited by 105 publications

(93 citation statements)

References 29 publications

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“…In never-smokers, we have identified NEXN (nexilin F-actin binding protein) as the putative causal gene on 1p31.1. 22 NEXN seems to confer protection against atherosclerosis by suppressing inflammatory cytokines (IL-6 and TNFα), adhesion molecules (ICAM1, VCAM1 and MCP1) and extracellular matrix-degrading enzymes (MMP1 and MMP9). Mutations in this gene have been associated with cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent study demonstrated that the expression levels of NEXN-AS1 and NEXN are decreased in human atherosclerotic plaques and NEXN deficiency promotes atherosclerosis in an experimental mouse model. 22 NEXN seems to confer protection against atherosclerosis by suppressing inflammatory cytokines (IL-6 and TNFα), adhesion molecules (ICAM1, VCAM1 and MCP1) and extracellular matrix-degrading enzymes (MMP1 and MMP9). The control exerted by NEXN on these molecular processes may also come into play in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome‐wide association study reveals candidate causal genes for lung cancer

Bossé

Xia

et al. 2019

Intl Journal of Cancer

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We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome‐wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never‐ and ever‐smokers). We performed replication analysis using lung data from the Genotype‐Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever‐smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3‐adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptome‐wide association study reveals candidate causal genes for lung cancer

Bossé

Xia

et al. 2019

Intl Journal of Cancer

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“…In addition to endothelial cells, NEXN-AS1 was also shown to modulate NEXN expression in monocytes and VSMCs. NEX-N +/− ApoE −/− mice (NEXN −/− ApoE −/− mice were embryonically lethal) had substantially increased atherosclerotic burden and thinner cap fibroatheroma than ApoE −/− mice, indicating that NEXN plays a protective role against the development of vulnerable atherosclerotic plaques and atherosclerosis [88].…”

Section: Lncrnas In Endothelial Cells (Ecs)mentioning

confidence: 99%

Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases

Yeh

Chang

et al. 2020

J Biomed Sci

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With the advances in deep sequencing-based transcriptome profiling technology, it is now known that human genome is transcribed more pervasively than previously thought. Up to 90% of the human DNA is transcribed, and a large proportion of the human genome is transcribed as long noncoding RNAs (lncRNAs), a heterogenous group of non-coding transcripts longer than 200 nucleotides. Emerging evidence suggests that lncRNAs are functional and contribute to the complex regulatory networks involved in cardiovascular development and diseases. In this article, we will review recent evidence on the roles of lncRNAs in the biological processes of cardiovascular development and disorders. The potential applications of lncRNAs as biomarkers and targets for therapeutics are also discussed.

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“…For example, the lncRNA NEXN-AS1 has been shown to mitigate AS by regulating activity of the actin-binding protein NEXN. 9 The lncRNA taurine up-regulated gene 1 (TUG1) is located on chromosome 22q12.2 and has a length of 7.1 kb; it was originally identified in taurine-treated mouse retinal cells. 10 Increasing evidence indicates that the dysregulation of TUG1 is involved in the development of a variety of diseases including cancer, ischemic stroke, and diabetes.…”

Section: Introductionmentioning

confidence: 99%

<p>Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA <em>TUG1</em> to Induce Autophagy and Inhibit Atherosclerosis</p>

You¹,

Long²,

Song³

et al. 2020

DDDT

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Background: Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS. Methods: First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS. Results: qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS. Conclusion: Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1.

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

Cited by 105 publications

References 29 publications

Transcriptome‐wide association study reveals candidate causal genes for lung cancer

Transcriptome‐wide association study reveals candidate causal genes for lung cancer

Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases

<p>Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA <em>TUG1</em> to Induce Autophagy and Inhibit Atherosclerosis</p>

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