Rpl13asnoRNAs降低平滑肌细胞COX4I2的调节,并促进新极端增生症
Brittany A Elliott1, Lisheng Zhang1, Jiao-Hui Wu1
1Department of Medicine (Cardiology), Duke University School of Medicine, Durham, NC.
bioRxiv : the preprint server for biology
|August 8, 2025
概括
Rpl13a小核细胞RNAs (snoRNAs) 通过增加活性氧物种 (ROS) 来驱动血管光滑肌肉细胞激活和新极端增生. 这些snoRNAs降低COX4I2表达的调节,从而导致更高的ROS水平并促进血管疾病.
科学领域:
- 心血管生物学 心血管生物学
- 分子生物学分子生物学
- 在RNA生物学,RNA生物学.
背景情况:
- 活性氧物种 (ROS) 在动脉损伤和动脉样硬化中加剧血管光滑肌细胞 (SMC) 激活和新极度增生.
- 由Rpl13a位点编码的小核细胞RNA (snoRNAs) 被确定为细胞ROS水平的关键调节者.
研究的目的:
- 调查Rpl13asnoRNAs在调节SMC激活和新极端增生症中的作用,体内和体外.
- 阐明Rpl13asnoRNAs影响ROS产生和SMC功能的分子机制.
主要方法:
- 使用Rpl13a的snoRNA淘汰赛 (snoKO) 小鼠和野生类型 (WT) 的 littermates.
- 在小鼠中通过动脉内皮脱皮诱导的neointimal增生.
- 在WT和snoKO小鼠的初级SMC上进行了体外功能测定和蛋白质组分析.
- 在HEK293T细胞中研究了snoRNA引导的mRNA2'-O-甲基化,具有特定的snoRNA删除.
主要成果:
- 与WT小鼠相比,snoKO小鼠表现出降低的动脉ROS,炎症和新极度增生.
- 在体外,snoKO SMCs显示ROS,迁移,增殖和炎症信号的降低.
- 在snoKO SMCs和大动脉中减少的ROS与线粒体COX4I2蛋白增加相关,这是线粒体ROS的调节者.
- 在HEK293T细胞中删除U32AsnoRNA减少了COX4I2mRNA的2'-O-甲基化,从而调节了COX4I2蛋白.
结论:
- Rpl13a snoRNAs是SMC激活和新极端增生症的关键驱动因素.
- Rpl13a的snoRNA会提高SMC的ROS水平,部分是通过对COX4I2表达的转录后下调.
- 向Rpl13asnoRNAs可能提供一种治疗策略,用于预防或治疗与新极度增生症相关的血管疾病.
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