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

Wenxing Cui,Yan Qu,Xun Wu,Wei Guo,Dayun Feng,Shunnan Ge,Yingwu Shi,Liang Wang,Jianing Luo,Haixiao Liu,Qiang Wang

doi:10.1007/s12264-021-00681-0

Wenxing Cui, Yan Qu + Show 9 more

Open Access

https://doi.org/10.1007/s12264-021-00681-0

Copy DOI

Journal: Neuroscience Bulletin	Publication Date: May 3, 2021
Citations: 5	License type: open-access

Affiliation: Air Force Medical University

Abstract

Traumatic brain injury (TBI)-induced coagulopathy 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 transcriptome 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.

Highlights

Traumatic brain injury (TBI) constitutes a significant proportion of global injuries, and remains one of the major causes of traumatic death and disability [1]
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 and transcriptome analysis indicated that acrolein over-activated autophagy, and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/ mTOR pathway

Summary

Introduction

Traumatic brain injury (TBI) constitutes a significant proportion of global injuries, and remains one of the major causes of traumatic death and disability [1]. Despite advances in the treatment of TBI, a high risk of poor outcomes still exists in these patients. Coagulopathy is a common secondary injury in TBI patients, occurring in 33% to 66% of cases, due to the different detection methods and definitions [2, 3]. TBIinduced coagulopathy is consistently associated with poor outcomes [4, 5], and these patients tend to suffer from progressive intracranial hemorrhage and microvascular thrombosis [6, 7]. TBI-induced coagulopathy follows a distinct pathogenic pathway. The incidence of coagulopathy after TBI is higher than that after traumatic injuries of other organs. Isolated TBI can induce early and systemic coagulopathy, even without substantial blood loss and hemodilution because of fluid resuscitation [8]. Previous studies have shown that TBI-induced coagulopathy manifests as a hypercoagulable state induced by pro-coagulant molecules

Objectives

Methods

Results

Conclusion