文献检索文档翻译深度研究
Suppr Zotero 插件Zotero 插件
邀请有礼套餐&价格历史记录

新学期，新优惠

限时优惠:9月1日-9月22日

30天高级会员仅需29元

1天体验卡首发特惠仅需5.99元

了解详情
不再提醒
插件&应用
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
高级版
套餐订阅购买积分包
AI 工具
文献检索文档翻译深度研究
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2025

内皮细胞 ROBO4 抑制 PTGS2/COX-2 的表达并减轻炎症性疾病。

Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases.

机构信息

Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.

出版信息

Commun Biol. 2024 May 18;7(1):599. doi: 10.1038/s42003-024-06317-z.

DOI:10.1038/s42003-024-06317-z
PMID:38762541
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11102558/
Abstract

Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases.

摘要

越来越多的证据表明，内皮细胞可以作为有治疗价值的靶点。其中一个潜在的靶点是内皮细胞特异性蛋白，Roundabout4（ROBO4）。研究表明，ROBO4 可以改善包括传染病和败血症在内的多种疾病的小鼠模型，但它的作用机制尚不完全清楚。在这项研究中，我们通过 RNA-seq 分析发现，ROBO4 下调前列腺素内过氧化物合酶 2（PTGS2）的表达，PTGS2 编码环氧化酶-2。机制分析表明，ROBO4 与含有 IQ 基序的 GTP 酶激活蛋白 1（IQGAP1）和 TNF 受体相关因子 7（TRAF7）相互作用，TRAF7 是一种泛素 E3 连接酶。在这个复合物中，ROBO4 通过 TRAF7 增强 IQGAP1 的泛素化，抑制 RAC1 的持续激活，并减少炎症性内皮细胞中 PTGS2 的表达。此外，ROBO4 基因敲除的小鼠会加剧与 PTGS2 相关的炎症性疾病，包括关节炎、水肿和疼痛。因此，我们揭示了 ROBO4 抑制炎症反应和血管通透性增加的分子机制，强调了它作为炎症性疾病有治疗前景的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/53d2facfb3c8/42003_2024_6317_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/4f5b92c47236/42003_2024_6317_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/b807a9e4b5d1/42003_2024_6317_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/8cd73b2a70fe/42003_2024_6317_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/32240852de6d/42003_2024_6317_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/f5034937e64c/42003_2024_6317_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/2c88c5f746b7/42003_2024_6317_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/53d2facfb3c8/42003_2024_6317_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/4f5b92c47236/42003_2024_6317_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/b807a9e4b5d1/42003_2024_6317_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/8cd73b2a70fe/42003_2024_6317_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/32240852de6d/42003_2024_6317_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/f5034937e64c/42003_2024_6317_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/2c88c5f746b7/42003_2024_6317_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bbc/11102558/53d2facfb3c8/42003_2024_6317_Fig7_HTML.jpg

相似文献

[1]
Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases.

Commun Biol. 2024-5-18

[2]
The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation.

J Cell Sci. 2019-1-2

[3]
HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells.

Tissue Barriers. 2021-7-3

[4]
New mechanisms and therapeutic approaches to regulate vascular permeability in systemic inflammation.

Curr Opin Hematol. 2025-5-1

[5]
Upregulation of Robo4 expression by SMAD signaling suppresses vascular permeability and mortality in endotoxemia and COVID-19 models.

Proc Natl Acad Sci U S A. 2023-1-17

[6]
Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia.

J Immunol. 2013-11-22

[7]
Silencing of directional migration in roundabout4 knockdown endothelial cells.

BMC Cell Biol. 2008-11-3

[8]
Tumor Necrosis Factor α Induces the Expression of the Endothelial Cell-Specific Receptor Roundabout4 through the Nuclear Factor-κB Pathway.

Biol Pharm Bull. 2017

[9]
Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis.

Mol Oncol. 2016-2

[10]
Roundabout4 suppresses glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated PI3K/AKT and FAK signaling pathways.

Cell Physiol Biochem. 2015

引用本文的文献

[1]
Review of the Role of TRAF7 in Brain Endothelial Integrity and Cerebrovascular Aging.

Life (Basel). 2025-8-12

[2]
Machine learning identification of key genes in cardioembolic stroke and atherosclerosis: their association with pan-cancer and immune cells.

Eur J Med Res. 2025-7-24

[3]
How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.

Front Mol Neurosci. 2025-6-25

[4]
PTGS2 Silencing Inhibits Ferroptosis in Staphylococcus Aureus-induced Osteomyelitis By Blocking the IL-17A Signaling Pathway.

Inflammation. 2025-4-21

[5]
Investigating the pharmacological mechanisms of clopidogrel for carotid stenosis treatment based on network pharmacology and molecular docking techniques.

Clin Exp Med. 2025-3-14

[6]
Curdione combined with borneol treats bacterial mixed HPV infection by regulating the crosstalk among immune cells.

Front Immunol. 2025-1-22

本文引用的文献

[1]
TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.

iScience. 2023-7-25

[2]
Upregulation of Robo4 expression by SMAD signaling suppresses vascular permeability and mortality in endotoxemia and COVID-19 models.

Proc Natl Acad Sci U S A. 2023-1-17

[3]
SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression.

Sci Adv. 2022-9-23

[4]
Immunomodulation by endothelial cells - partnering up with the immune system?

Nat Rev Immunol. 2022-9

[5]
HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells.

Tissue Barriers. 2021-7-3

[6]
The effective interplay of (non-) selective NSAIDs with neostigmine in animal models of analgesia and inflammation.

BMC Pharmacol Toxicol. 2021-5-1

[7]
Vascular Endothelial Cells and Innate Immunity.

Arterioscler Thromb Vasc Biol. 2020-5-27

[8]
Ubiquitination of the scaffold protein IQGAP1 diminishes its interaction with and activation of the Rho GTPase CDC42.

J Biol Chem. 2020-2-24

[9]
The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation.

J Cell Sci. 2019-1-2

[10]
GENCODE reference annotation for the human and mouse genomes.

Nucleic Acids Res. 2019-1-8

文献AI研究员

20分钟写一篇综述，助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

推荐工具

医学文档翻译智能文献检索