在Srsf3-依赖的APA驱动巨细胞成熟和限制动脉样硬化
Xian Yang1, Xin Zhang1, Yaru Tian1
1Department of Immunology, School of Basic Medical Sciences, and Department of Rheumatology, Zhongshan Hospital (X.Y., X.Z., Y.T., J.Y., Y.J., Y.X., L.C., S.C., L.W., Y.Q., Y.W.), Fudan University, Shanghai, China.
Circulation research
|March 31, 2025
概括
富含氨酸/氨酸的剪接因子3 (Srsf3) 在动脉样硬化中促进巨细胞的成熟和功能. 缺少Srsf3会损害线粒体翻译,导致成熟延迟和动脉样硬化加重,但NAD+前体可以帮助.
科学领域:
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
- 心血管研究研究心血管研究
背景情况:
- 循环单细胞在动脉样硬化斑块内分化为巨细胞,对于清除脂质和细胞残渣至关重要.
- 控制单细胞转变为巨细胞的精确机制以及替代多基化在动脉生成中的作用尚未完全理解.
研究的目的:
- 为了研究动脉样硬化中的单细胞/巨细胞亚型.
- 确定替代多基化,特别是由氨酸/氨酸丰富的剪接因子3 (Srsf3) 调节的替代多基化对这些细胞类型和疾病进展的影响.
主要方法:
- 单细胞RNA测序,3'-end测序和流动细胞测量用于与或没有髓质Srsf3缺失的小鼠动脉样斑块.
- 细胞和分子测试,包括多体样化和代谢学,阐明了潜在的机制.
- 人类斑块被分析为替代的多基化模式和巨细胞种群.
主要成果:
- 在病变中确定了过渡性单细胞巨细胞的一个子集.
- 删除Srsf3延迟了过渡细胞成熟,损害了巨细胞化,并恶化了动脉样硬化.
- 缺乏Srsf3导致Aars2的3' UTR缩短,破坏线粒体翻译,NAD+水平,并激活压力反应.
- NAD+前体或压力反应抑制剂部分恢复了Srsf3缺乏的巨细胞功能并减轻了动脉样硬化.
结论:
- 长3' UTRs依赖于Srsf3,对于线粒体翻译和成熟的细胞巨细胞的发展至关重要.
- 这一过程通过促进功能性巨细胞分化,在动脉样硬化中起着保护作用.
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