ATF3 缺乏症加剧衰老引起的动脉样硬化和临床干预策略
Hao Nie1,2, Tianyi Ji1,2, Zixin Wan1
1Department of Geriatrics, Key Laboratory of Vascular ageing, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|July 11, 2025
概括
激活转录因子3 (ATF3) 通过激活自,可以防止血管光滑肌肉细胞衰老和动脉样硬化. 重用现在稳定ATF3,为与年龄有关的心血管疾病提供治疗策略.
科学领域:
- 心血管生物学 心血管生物学
- 分子衰老 分子衰老
- 细胞衰老 细胞衰老
背景情况:
- 血管光滑肌细胞 (VSMC) 衰老驱动动动动脉样硬化 (AS),但其在衰老中的分子调节知之甚少.
- 识别VSMC衰老的关键调节者对于开发针对与年龄有关的心血管疾病的干预措施至关重要.
研究的目的:
- 确定VSMC衰老的新型调节剂,并探索与年龄相关的AS的治疗策略.
- 阐明激活转录因子3 (ATF3) 影响VSMC衰老和AS的分子机制.
主要方法:
- 用SMC特定的ATF3淘汰赛小鼠对人类大动脉的单细胞RNA测序,免疫光和体内研究.
- CUT&Tag-seq,RNA-蛋白相互作用测定,m6A表谱分析,以及针对ATF3向化合物的高通量虚拟查.
- 确定化合物的功能验证和ATF3-ATG7反循环和Atf3mRNA的m6A修饰的机制研究.
主要成果:
- 确定ATF3是VSMC衰老的中央调节者,ATF3缺乏会加速老化引起的AS.
- 发现了一种新的正反循环,ATF3激活ATG7,促进自,细胞质ATG7增强ATF3的核转移.
- 与年龄相关的m6A甲基化破坏了Atf3mRNA的稳定;通过抑制YTHDF2相互作用,现在osin (TZ) 稳定了Atf3mRNA,从而保持了ATF3水平.
结论:
- 通过ATF3-ATG7放大循环,ATF3通过编排自来保护VSMC衰老和AS.
- 通过重新定位 terazosin 来稳定 ATF3 是一种可翻译的治疗方法来缓解因衰老而导致的心血管疾病.
- 这些发现为VSMC衰老的分子机制提供了关键的见解,并为治疗与年龄相关的动脉样硬化提供了潜在的策略.
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