骨髓细胞Drp1缺乏限制了通过炎症性巨分化和代谢重编程在缺血性肌肉中的再血管化
bioRxiv : the preprint server for biology
|November 14, 2023
概括
线粒体分裂蛋白Drp1对于外周动脉疾病 (PAD) 模型的愈合至关重要. 巨细胞Drp1缺陷通过促进炎症和代谢功能障碍,损害了重血管化.
科学领域:
- 线粒体动力学的动态
- 巨生物学的生物学
- 血管生物学 血管生物学
背景情况:
- 周围动脉疾病 (PAD) 需要抗炎性巨细胞两极分化和血管生成来进行再血管化.
- 巨细胞代谢和炎症与线粒体动力学有关.
- 线粒体分裂蛋白DRP1在巨细胞炎症中具有上下文依赖的作用.
研究的目的:
- 在临床前PAD模型中调查巨Drp1在修复性新血管化中的作用.
- 阐明Drp1通过哪些机制影响胰岛素缺血中的巨细胞极化和新陈代谢.
主要方法:
- 使用后肢缺血 (HLI) 鼠标模型,这是PAD的临床前模型.
- 产生的骨髓细胞特异性Drp1淘汰赛 (Drp1-/-) 小鼠.
- 分析了巨细胞两极分化 (M1/M2),炎症标记物 (p-NFkB,TNFα),代谢标记物 (p-AMPK),线粒体功能和缺血肌肉中的ROS.
- 使用Drp1-/-巨细胞采用体外低氧血清饥饿 (HSS) 模型.
- 从经过治疗的巨细胞中评估了内皮细胞对条件介质的血管性反应.
主要成果:
- 在HLI后的缺血性肌肉中的巨细胞中,drp1的表达增加.
- 骨髓细胞特异性Drp1缺陷减少了四肢 perfusion 恢复,血管新生和肌肉再生.
- Drp1 缺乏增强了M1 类巨细胞和前炎性标记物,同时减少了M2 类巨细胞和p-AMPK.
- 在体外,Drp1-/-巨细胞显示了增强的糖解,线粒体功能障碍,增加的ROS,M1极化和减少的M2极化.
- 来自Drp1-/-巨细胞的条件介质抑制了内皮细胞血管生成.
结论:
- 在实验性PAD模型中,巨细胞Drp1缺乏会加剧炎症和代谢功能障碍.
- 在缺血期间,drp1在调节巨细胞代谢重编程和极化方面发挥着至关重要的作用.
- 向巨细胞Drp1可能提供一种治疗策略,以改善PAD的重血管化.
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