新型组蛋白去乙酰化酶抑制剂 W2A-16 可改善脑血管内皮细胞屏障的完整性

IF 4.2 3区 医学 Q2 NEUROSCIENCES Frontiers in Cellular Neuroscience Pub Date : 2024-07-19 DOI:10.3389/fncel.2024.1368018
Yasuteru Inoue, Yingxue Ren, Shuwen Zhang, Michael Bamkole, Naeyma N. Islam, Manikandan Selvaraj, Wenyan Lu, Thomas R. Caulfield, Yonghe Li, Takahisa Kanekiyo
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引用次数: 0

摘要

脑微血管内皮细胞成熟后会形成一个紧密密封的单层,即血脑屏障(BBB)。血脑屏障损伤与血管性认知障碍和阿尔茨海默病等与年龄相关的神经退行性疾病的发病机制有关。表观遗传学领域不断增长的知识可以加深人们对 BBB 分子特征的了解,并具有开发新型治疗策略或靶点以修复被破坏的 BBB 的巨大潜力。组蛋白去乙酰化酶(HDACs)抑制剂是一种表观遗传调节剂,可诱导组蛋白乙酰化并诱导染色质开放构象,通过增强 DNA 与转录因子的结合促进基因表达。我们使用永生化人内皮细胞(HCMEC/D3)和诱导多能干细胞(iPSC)衍生的脑血管内皮细胞研究了 HDAC 抑制如何影响屏障完整性。使用或不使用一种名为 W2A-16 的新型化合物处理内皮细胞。W2A-16 不仅能激活 Wnt/β-catenin 信号转导,而且还是一种 I 类 HDAC 抑制剂。我们证实,服用 W2A-16 能维持内皮细胞单层的屏障特性,表现为跨内皮电阻(TEER)的增加。与未经处理的对照组相比,与 BBB 相关的基因和蛋白质表达也有所增加。通过对 hCMEC/D3 细胞中的 RNA 序列进行转录谱分析表明,W2A-16 有可能通过影响与细胞外微环境调控相关的基因来增强 BBB 的完整性。这些发现共同表明,W2A-16 对 HDAC 的抑制在 BBB 的形成过程中起到了促进作用。抑制 HDAC 的药理方法可能是促进和/或恢复 BBB 完整性的潜在治疗策略。
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A novel histone deacetylase inhibitor W2A-16 improves the barrier integrity in brain vascular endothelial cells
The maturation of brain microvascular endothelial cells leads to the formation of a tightly sealed monolayer, known as the blood–brain barrier (BBB). The BBB damage is associated with the pathogenesis of age-related neurodegenerative diseases including vascular cognitive impairment and Alzheimer’s disease. Growing knowledge in the field of epigenetics can enhance the understanding of molecular profile of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. Histone deacetylases (HDACs) inhibitors are epigenetic regulators that can induce acetylation of histones and induce open chromatin conformation, promoting gene expression by enhancing the binding of DNA with transcription factors. We investigated how HDAC inhibition influences the barrier integrity using immortalized human endothelial cells (HCMEC/D3) and the human induced pluripotent stem cell (iPSC)-derived brain vascular endothelial cells. The endothelial cells were treated with or without a novel compound named W2A-16. W2A-16 not only activates Wnt/β-catenin signaling but also functions as a class I HDAC inhibitor. We demonstrated that the administration with W2A-16 sustained barrier properties of the monolayer of endothelial cells, as evidenced by increased trans-endothelial electrical resistance (TEER). The BBB-related genes and protein expression were also increased compared with non-treated controls. Analysis of transcript profiles through RNA-sequencing in hCMEC/D3 cells indicated that W2A-16 potentially enhances BBB integrity by influencing genes associated with the regulation of the extracellular microenvironment. These findings collectively propose that the HDAC inhibition by W2A-16 plays a facilitating role in the formation of the BBB. Pharmacological approaches to inhibit HDAC may be a potential therapeutic strategy to boost and/or restore BBB integrity.
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来源期刊
CiteScore
7.90
自引率
3.80%
发文量
627
审稿时长
6-12 weeks
期刊介绍: Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
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