Acrolein Induces Systemic Coagulopathy via Autophagy-depen-dent Secretion of von Willebrand Factor in Mice after Traumatic Brain Injury

• 作者: Wenxing Cui Xun Wu Dayun Feng Jianing Luo Yingwu Shi Wei Guo Haixiao Liu Qiang Wang Liang Wang Shunnan Ge Yan Qu
• 来源期刊: 神经科学通报（英文版）
• 年，卷（期）: 2021,（8）
• 所属期刊栏目: Original Articles
• 页码范围: 1160-1175
• 页数: 16页
• 语种: 英文

摘要

Traumatic brain injury (TBI)-induced coagu-lopathy has increasingly been recognized as a significant risk factor for poor outcomes,but the pathogenesis remains poorly understood.In this study,we aimed to investigate the causal role of acrolein,a typical lipid peroxidation product,in TBI-induced coagulopathy,and further explore the underlying molecular mechanisms.We found that the level of plasma acrolein in TBI patients suffering from coagulopathy was higher than that in those without coagulopathy.Using a controlled cortical impact mouse model,we demonstrated that the acrolein scavenger phenelzine prevented TBI-induced coagulopathy and recombinant ADAMTS-13 prevented acrolein-induced coagulopathy by cleaving von Willebrand factor (VWF).Our results showed that acrolein may contribute to an early hypercoagulable state after TBI by regulating VWF secretion,mRNA sequencing (mRNA-seq) and transcrip-tome analysis indicated that acrolein over-activated autophagy,and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/mTOR pathway.In addition,we demonstrated that acrolein was produced in the perilesional cortex,affected endothelial cell integrity,and disrupted the blood-brain barrier.In conclusion,in this study we uncovered a novel pro-coagulant effect of acrolein that may contribute to TBI-induced coagulopathy and vascular leakage,providing an alternative therapeutic target.