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DNA-PKcs 酸 Cofilin2 诱导内皮功能障碍和微循环障碍在内毒性心肌病症内

Yingzhen Du¹, Pingjun Zhu¹, Yukun Li²

¹The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China.

Research (Washington, D.C.)

|March 29, 2024

概括

依赖DNA的蛋白激酶催化子单元 (DNA-PKcs) 通过破坏内皮功能而加剧内毒性心肌病. 抑制DNA-PKcs或其cofilin2酸化可以在败血症期间保护心脏微血管.

科学领域:

心血管生物学心血管生物学
分子医学是分子医学.
内皮细胞生物学内皮细胞生物学

背景情况:

内毒性导致内皮功能障碍和心肌微血管损伤,导致心肌病.
依赖DNA的蛋白激酶催化子单元 (DNA-PKcs) 涉及到与败血症相关的器官损伤.
DNA-PKcs在内毒素引起的内皮和心肌微血管功能障碍中的作用尚不清楚.

研究的目的:

调查DNA-PKcs在内皮和心肌微血管功能障碍在内毒性病期间的作用.
阐明DNA-PKcs导致内毒性心肌病的分子机制.

主要方法:

在小鼠中进行的临床实验中,发现了脂聚糖 (LPS) 诱导的内毒性心肌病.
在初级小鼠心脏微血管内皮细胞中进行测试.
使用内皮细胞特异性DNA-PKcs切除和cofilin2-knockin小鼠模型.

主要成果:

内皮DNA-PKcs切除改善了内皮血管输液,内皮屏障功能和内毒性小鼠的心脏功能.
DNA-PKcs在Thr25处酸化cofilin2,增强其F-actin结合并促进脱聚合.
缺陷的cofilin2突变小鼠在内毒性病期间表现出改善的内皮和微血管功能.

结论:

在内毒症期间,DNA-PKcs在调解心脏微血管功能障碍方面发挥着关键作用.
DNA-PKcs在Thr25处诱导cofilin2酸化,导致F-actin脱聚合和内皮屏障破坏.
向DNA-PKcs-cofilin2通路为内毒性相关心脏功能障碍提供了潜在的治疗策略.

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