激活USP30会破坏内皮细胞功能,并通过调节S-腺甲氨酸循环来加剧急性肺损伤
Baoyinna Baoyinna1, Jinshan He1,2, Jiaxing Miao1
1Department of Physiology and Cell Biology, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|October 17, 2025
概括
USP30调节肺部微血管炎症和内皮细胞屏障完整性. 抑制USP30可以减少炎症反应,并通过调节S-adenosylmethionine循环和microRNA表达来防止急性肺损伤.
科学领域:
- 血管生物学 血管生物学
- 炎症研究 炎症研究
- 分子医学是分子医学.
背景情况:
- 微血管功能障碍,以增加血管透性和白细胞透为特征,是急性炎症性疾病的核心.
- 微血管功能障碍背后的精确分子机制仍然不完全理解.
- 内皮细胞 (EC) 屏障完整性对于在炎症期间维持血管平衡至关重要.
研究的目的:
- 为了确定肺微血管炎症和EC屏障功能的关键调节者.
- 研究USP30在调节内皮细胞对炎症刺激反应中的作用.
- 阐明USP30影响EC功能障碍和急性肺损伤的分子机制.
主要方法:
- 利用脂聚糖 (LPS) 诱导内皮细胞和体内模型中的炎症.
- 在小鼠的内皮细胞中使用USP30的遗传删除.
- 研究了USP30抑制对S-adenosylmethionine (SAM) 循环,DNA甲基化和microRNA表达的影响.
- 在对USP30调制的反应中评估了炎症标志物,EC屏障功能和微血管功能障碍.
主要成果:
- USP30二维基丁酶活性是由LPS诱导的,并加剧了EC功能障碍.
- 抑制USP30可显著减轻约50%的ECs的炎症反应.
- 欧盟特异性USP30缺乏的小鼠在内毒素诱导和缺血-再输液肺损伤模型中显示出减少的微血管功能障碍.
- 抑制USP30通过一种与髓无关的途径保持EC功能,包括降低MAT2A,降低SAM水平 (~40%),降低全球DNA甲基化 (~35%),导致miR-30a-5p上调.
- 上调的miR-30a-5p抑制了MDM2和NFAT5,维持了EC功能.
结论:
- USP30是肺微血管炎症和EC屏障完整性的关键调节者.
- 针对USP30代表了急性肺损伤的潜在治疗策略.
- 抑制USP30通过一种涉及SAM循环,DNA甲基化和miR-30a-5p的新机制来保护EC功能.
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