Tudor-SN 通过 NEDD4-1 促进 PTEN 的多泛素化,从而加剧病理性血管重塑。

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-09-05 DOI:10.1186/s12929-024-01076-9
Yichen Wu, Zilong Chen, Zhe Zheng, Xiaoguang Li, Jiangcheng Shu, Ruiqi Mao, Jie An, Siyuan Fan, Ruijie Luo, Yi Guo, Wenjing Xu, Minglu Liang, Kai Huang, Cheng Wang
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引用次数: 0

摘要

背景:血管稳态失调可诱发心血管疾病并增加全球死亡率。尽管品系追踪研究已证实血管平滑肌细胞(VSMC)在病理血管重塑过程中起着关键作用,但其潜在机制仍不清楚:方法:在动脉狭窄的血管平滑肌细胞、PDGF-BB 处理的血管平滑肌细胞和动脉粥样硬化斑块中检测 Tudor-SN 的表达。采用功能缺失和功能增益方法探讨了 Tudor-SN 在体内和体外调节 VSMC 表型中的作用:结果:在这项研究中,我们证明了Tudor-SN在损伤诱导的动脉、动脉粥样硬化斑块和PDGF-BB刺激的VSMCs中表达显著升高。Tudor-SN的缺失可减轻VSMCs的合成表型转换和病理血管重塑,但过表达则会加重VSMCs的合成表型转换和病理血管重塑。Tudor-SN 的缺失也会减少动脉粥样硬化斑块的形成并增加斑块的稳定性。从机理上讲,PTEN 是 MAPK 和 PI3K-AKT 信号通路的主要调节因子,在 Tudor-SN 介导的 VSMC 增殖和迁移调节中发挥着重要作用。Tudor-SN 通过 NEDD4-1 促进 PTEN 的多泛素化和降解,从而在病理条件下加剧血管重塑。PTEN的特异性抑制剂BpV(HOPIC)不仅能抵消Tudor-SN缺乏对VSMC增殖和迁移的保护作用,还能消除颈动脉损伤诱导的小鼠血管重塑的负面影响:我们的研究结果表明,通过减少 NEDD4-1 依赖性 PTEN 多泛素化,Tudor-SN 的缺乏能显著改善病理性血管重塑,这表明 Tudor-SN 可能是预防血管疾病的一个新靶点。
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Tudor-SN exacerbates pathological vascular remodeling by promoting the polyubiquitination of PTEN via NEDD4-1.

Background: Dysregulation of vascular homeostasis can induce cardiovascular diseases and increase global mortality rates. Although lineage tracing studies have confirmed the pivotal role of modulated vascular smooth muscle cells (VSMCs) in the progression of pathological vascular remodeling, the underlying mechanisms are still unclear.

Methods: The expression of Tudor-SN was determined in VSMCs of artery stenosis, PDGF-BB-treated VSMCs and atherosclerotic plaque. Loss- and gain-of-function approaches were used to explore the role of Tudor-SN in the modulation of VSMCs phenotype both in vivo and in vitro.

Results: In this study, we demonstrate that Tudor-SN expression is significantly elevated in injury-induced arteries, atherosclerotic plaques, and PDGF-BB-stimulated VSMCs. Tudor-SN deficiency attenuates, but overexpression aggravates the synthetic phenotypic switching of VSMCs and pathological vascular remodeling. Loss of Tudor-SN also reduces atherosclerotic plaque formation and increases plaque stability. Mechanistically, PTEN, the major regulator of the MAPK and PI3K-AKT signaling pathways, plays a vital role in Tudor-SN-mediated regulation on proliferation and migration of VSMCs. Tudor-SN facilitates the polyubiquitination and degradation of PTEN via NEDD4-1, thus exacerbating vascular remodeling under pathological conditions. BpV (HOpic), a specific inhibitor of PTEN, not only counteracts the protective effect of Tudor-SN deficiency on proliferation and migration of VSMCs, but also abrogates the negative effect of carotid artery injury-induced vascular remodeling in mice.

Conclusions: Our findings reveal that Tudor-SN deficiency significantly ameliorated pathological vascular remodeling by reducing NEDD4-1-dependent PTEN polyubiquitination, suggesting that Tudor-SN may be a novel target for preventing vascular diseases.

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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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