停止获得的VEGFA变体恶化了心肌梗塞中心脏重塑的情况
Zhongxiang Chen1, Diqi Zhu1, Kaa Seng Lai2
1Department of Pediatric Cardiology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, China (Z.C., D.Z., Y.C., Y.H., Z.Y., F.L.).
Circulation. Genomic and precision medicine
|July 18, 2025
概括
血管内皮生长因子A (VEGFA) 剂量对心脏健康至关重要. 一种特定的基因变异损害了VEGFA的产生,通过改变细胞微环境,在心肌梗塞后恶化了心脏功能.
科学领域:
- 心血管生物学 心血管生物学
- 分子遗传学 分子遗传学
- 血管新生研究研究
背景情况:
- 血管内皮生长因子A (VEGFA) 在正常生理和心血管疾病中对血管形成至关重要.
- 来自CUG编码子的替代翻译启动产生成熟的VEGFA,这一过程是某些遗传变异的目标.
- 停止增益变体对血管健康的影响,这些变体过早终止CUG启动的翻译,尚不清楚.
研究的目的:
- 研究VEGFA停止增益变异对心脏血管系统的功能后果.
- 使用CRISPR/Cas9生成的小鼠等位基因 (Q150X) 建模人类VEGFA变异.
- 评估VEGFA剂量在心脏平衡和心肌梗塞 (MI) 后的作用.
主要方法:
- 使用CRISPR/Cas9.9生成了一个小鼠模型 (Q150X/Q150Vegfa),模仿人类停止获得的VEGFA变体.
- 在恒温和急性心肌梗塞 (MI) 条件下评估心血管结构.
- 采用免疫光学,光片成像,单核RNA测序和转录组学/表观组学来分析细胞和分子变化.
主要成果:
- 带有VEGFA Q150X变异的小鼠显示VEGFA水平降低 (在恒温状态下70%;在MI后40%),但是可行的.
- Q150X变种导致心脏病后心脏功能恶化.
- 内皮细胞表现出增加的缺氧压力和炎症;在缺血区中,应激的心肌细胞和炎症性免疫细胞得到了丰富.
结论:
- 由CUG发起的翻译对缺血性心脏中的VEGFA产生有显著的贡献.
- 在缺血损伤期间,VEGFA剂量是细胞微环境的关键决定因素.
- 针对VEGFA翻译可能为心血管疾病提供治疗策略.
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