位点特异性 m6A-miR-494-3p 而非未甲基化的 miR-494-3p,通过靶向颅内动脉粥样硬化中的紧密连接蛋白 1 破坏血脑屏障。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Tamar Woudenberg, M Leontien van der Bent, Veerle Kremer, Ingeborg S E Waas, Mat J A P Daemen, Reinier A Boon, Paul H A Quax, A Yaël Nossent
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引用次数: 0

摘要

背景和目的:颅内动脉粥样硬化是缺血性脑卒中最常见的病因之一。然而,人们对颅内动脉粥样硬化的发展还缺乏足够的了解。颅内动脉的特点是内皮细胞之间的紧密连接上调,而紧密连接控制着内皮的通透性。我们研究了 N6-甲基腺苷(m6A)这种常见的 RNA 修饰对内皮完整性的作用,重点研究了促动脉粥样硬化的 microRNA miR-494-3p、紧密连接蛋白 TJP1 和 PECAM1:实验方法:我们评估了不同阶段内膜增厚和斑块形成的死后人类椎动脉(VA)、颈内动脉(ICA)和大脑中动脉(MCA)中的 m6A 情况以及 miR-494-3p、TJP1 和 PECAM1 的表达。利用原代人(脑)内皮细胞在体外研究了经 m6A 修饰的 miR-494-3p 模拟物、TJP1 和 PECAM1 之间的相互作用:主要结果:在受动脉粥样硬化影响的血管腔内膜中观察到 m6A 表达增加,同时 TJP1 和 PECAM1(而非 VE-cadherin)表达减少。m6A 和 miR-494-3p 在 VA 斑块管腔内壁的共定位被证实,这表明 miR-494-3p 在颅内动脉粥样硬化中的 m6A 甲基化。此外,miR-494-3p 的位点特异性 m6A 修饰导致脑微血管内皮细胞细胞-细胞连接处的 TJP1 蛋白表达受到特异性抑制,而未修饰的 miR-494-3p 则没有影响:本研究强调了颅内动脉粥样硬化发生过程中 m6A 水平的增加。m6A-miR-494-3p的增加导致了观察到的内皮细胞-细胞连接处TJP1表达的减少。这可能会对内皮完整性产生负面影响,从而加速颅内动脉粥样硬化的进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Site-specific m6A-miR-494-3p, not unmethylated miR-494-3p, compromises blood brain barrier by targeting tight junction protein 1 in intracranial atherosclerosis.

Background and purpose: Intracranial atherosclerosis is one of the most common causes of ischaemic stroke. However, there is a substantial knowledge gap on the development of intracranial atherosclerosis. Intracranial arteries are characterized by an upregulation of tight junctions between endothelial cells, which control endothelial permeability. We investigated the role of N6-methyladenosine (m6A), a common RNA modification, on endothelial integrity, focusing on the pro-atherogenic microRNA miR-494-3p and tight junction proteins TJP1 and PECAM1.

Experimental approach: We assessed the m6A landscape, along with the expression of miR-494-3p, TJP1 and PECAM1 in postmortem human vertebral arteries (VA), internal carotid arteries (ICA), and middle cerebral arteries (MCA) with various stages of intimal thickening and plaque formation. The interactions between m6A-modified miR-494-3p mimics, TJP1 and PECAM1, were investigated in vitro using primary human (brain) endothelial cells.

Key results: Increased m6A expression was observed in the luminal lining of atherosclerosis-affected VAs, accompanied by reduced TJP1 and PECAM1, but not VE-cadherin, expression. Colocalization of m6A and miR-494-3p in the luminal lining of VA plaques was confirmed, indicating m6A methylation of miR-494-3p in intracranial atherosclerosis. Moreover, site-specific m6A-modification of miR-494-3p led to repression specifically of TJP1 protein expression at cell-cell junctions of brain microvascular endothelial cells, while unmodified miR-494-3p showed no effect.

Conclusions and implications: This study highlights increasing m6A levels during intracranial atherogenesis. Increases in m6A-miR-494-3p contribute to the observed decreased TJP1 expression in endothelial cell-cell junctions. This is likely to have a negative effect on endothelial integrity and may thus accelerate intracranial atherosclerosis progression.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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