在动脉样硬化中,FOXO1集成了内皮血液动力学,炎症和代谢途径
Hanqiang Deng1,2, Xing Zhang1, Yewei Wang3
1Yale Cardiovascular Research Center (H.D., X.Z., D.J., M.A.S.), Yale University School of Medicine, New Haven, CT.
Circulation research
|February 25, 2026
概括
叉头盒蛋白O1 (FOXO1) 通过乳化将受损的血流与内皮炎症和动脉样硬化联系在一起. 生理流抑制FOXO1,这表明心血管疾病的新治疗点.
科学领域:
- 心血管生物学 心血管生物学
- 内皮细胞生物学 内皮细胞生物学
- 动脉样硬化的分子机制
背景情况:
- 动脉样硬化最好发生在流体剪切应力 (FSS) 受到干扰的区域,而层状FSS是保护性的.
- 内皮炎症与糖解有关,与抗炎性氧化酸化形成鲜明对比,但机制尚不清楚.
- 转录因子FOXO1调节内皮代谢和血管生成,但其在炎症中的作用尚不清楚.
研究的目的:
- 研究FOXO1在内皮炎症中的作用及其通过流体剪切应力调节的作用.
- 阐明FOXO1影响动脉样硬化发展的分子机制.
- 为了确定动脉样硬化心血管疾病的潜在治疗点.
主要方法:
- 内皮细胞在体外暴露于细胞因子或定义的流动模式.
- 检测包括免疫光,RNA测序和生物化学分析,以评估FOXO1.1.
- 在体内研究中使用了内皮细胞特异性FOXO1淘汰赛小鼠和诱导的高脂血症来模拟动脉样硬化.
主要成果:
- 扰乱的FSS和细胞因子促进FOXO1核转位,而生理FSS则抑制了它.
- FOXO1 枯竭调高了保护性转录因子 (KLF2/4) 和降低了炎症基因表达.
- 生理学FSS通过KLF2-CDK2信号抑制了FOXO1;乳酸盐通过乳化促进了FOXO1核定位.
- 在小鼠中,内皮细胞特异性FOXO1删除显著减少了动脉样硬化斑块.
结论:
- FOXO1作为一个关键的调解者,通过乳酸驱动的乳酸和核转位,将阿瑟罗流与内皮炎症联系起来.
- 生理学FSS通过KLF2-CDK2信号抑制FOXO1活动,提供一个反调节机制.
- 这些发现突出了FOXO1及其调节途径作为动脉样硬化心血管疾病的潜在治疗点.
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