活化 T 细胞核因子 5 是肺内皮细胞对缺氧做出平衡适应性转录反应所不可或缺的。

IF 10.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Hebatullah Laban, Sophia Siegmund, Katharina Schlereth, Felix A Trogisch, Alia Ablieh, Lennart Brandenburg, Andreas Weigert, Carolina De La Torre, Carolin Mogler, Markus Hecker, Wolfgang M Kuebler, Thomas Korff
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引用次数: 0

摘要

目的:慢性缺氧会导致肺部结构发生有害改变,从而可能引起肺动脉高压,这些改变部分是由内皮细胞介导的。尽管其与缺氧相关肺部疾病的发生发展的相关性已众所周知,但控制肺内皮对缺氧的初始适应的决定性因素在很大程度上仍未得到探索:我们发现缺氧会激活转录因子活化T细胞核因子5(NFAT5),并研究了它在小鼠肺内皮细胞(MLECs)中的调控功能。与对照组小鼠相比,暴露于常压缺氧(10% O2)21 天的小鼠肺内皮细胞特异性敲除 Nfat5(Nfat5(EC)-/-)会促进血管纤维化,加剧肺右室收缩压的升高和右室功能障碍。基于芯片和单细胞 RNA 序列的分析表明,缺失 Nfat5 的 MLEC 在缺氧 7 天后,生长因子、能量和蛋白质代谢相关基因表达受损。具体来说,NFAT5的缺失促进了血小板衍生生长因子B(Pdgfb)的表达和释放--这是一种由缺氧诱导因子1α(HIF1α)调控的血管平滑肌细胞(VSMC)生长驱动因子--缺氧暴露的Nfat5(EC)-/-小鼠的毛细血管MLEC中的血小板衍生生长因子B(Pdgfb)的表达和释放,与此同时,远端肺动脉的VSMC覆盖率增加:总之,我们的研究表明,MLEC 对缺氧的早期和短暂亚群特异性反应可能决定后期器官功能障碍的程度。在这种情况下,NFAT5 可作为一种保护性转录因子,迅速调整内皮转录组以应对缺氧。具体来说,NFAT5 限制了 HIF1α 介导的 Pdgfb 表达,从而限制了肺血管的肌肉化和阻力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nuclear factor of activated T-cells 5 is indispensable for a balanced adaptive transcriptional response of lung endothelial cells to hypoxia.

Aims: Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored.

Methods and results: We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs). EC-specific knockout of Nfat5 (Nfat5(EC)-/-) in mice exposed to normobaric hypoxia (10% O2) for 21 days promoted vascular fibrosis and aggravated the increase in pulmonary right ventricular systolic pressure as well as right ventricular dysfunction as compared with control mice. Microarray- and single-cell RNA-sequencing-based analyses revealed an impaired growth factor-, energy-, and protein-metabolism-associated gene expression in Nfat5-deficient MLEC after exposure to hypoxia for 7 days. Specifically, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B (Pdgfb)-a hypoxia-inducible factor 1 alpha (HIF1α)-regulated driver of vascular smooth muscle cell (VSMC) growth-in capillary MLEC of hypoxia-exposed Nfat5(EC)-/- mice, which was accompanied by intensified VSMC coverage of distal pulmonary arteries.

Conclusion: Collectively, our study shows that early and transient subpopulation-specific responses of MLEC to hypoxia may determine the degree of organ dysfunction in later stages. In this context, NFAT5 acts as a protective transcription factor required to rapidly adjust the endothelial transcriptome to cope with hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of the pulmonary vasculature.

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来源期刊
Cardiovascular Research
Cardiovascular Research 医学-心血管系统
CiteScore
21.50
自引率
3.70%
发文量
547
审稿时长
1 months
期刊介绍: Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases
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