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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurol. | doi: 10.3389/fneur.2018.00998

Endothelial Atg7 deficiency ameliorates acute cerebral injury induced by ischemia/reperfusion

 Hui-Jie Wang1, 2, Jia-Yi Wei1, 2, Dong-Xin Liu1, 2,  Shi-Fang Zhuang1, 2, Yuan Li1, 2, Hui Liu1, 2, Meng Ban1, 2, Wen-Gang Fang1, 2, Liu Cao1, 2,  Wei-Dong Zhao1, 2* and  Yu-Hua Chen1, 2*
  • 1Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, China
  • 2China Medical University, China


Ischemic strokes often result in cerebral injury due to ischemia/reperfusion (I/R). Although the local inflammatory responses are known to play a primary role in the brain I/R injury, the underlying mechanism remains unclear. In the current study, we investigated the effect of brain endothelial Atg7 (autophagy related 7) depletion in the acute brain injury induced by ischemia and reperfusion. Endothelial knockout of Atg7 in mice (Atg7 eKO) was found to significantly attenuate both the infarct volume and the neurological defects induced by I/R when compared to the controls. In fact, brain inflammatory responses induced by I/R were alleviated by the Atg7 eKO. Furthermore, an increased expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8 and TNF-α, was observed in brain endothelial cells in response to oxygen/glucose depletion/reoxygenation, which was decreased by the shRNA-mediated Atg7 knockdown. Interestingly, Atg7 knockdown reduced IKKβ phosphorylation, leading to NF-κB deactivation and downregulation of the pro-inflammatory cytokines mRNA levels. Further, Atg7 transcriptional regulation function is independent of its role in autophagy. Taken together, our results demonstrated that brain endothelial Atg7 contributes to brain damage during I/R by modulating the expression of pro-inflammatory cytokines. Depletion of Atg7 in brain endothelium has a neuroprotective effect against the ischemia/reperfusion-induced acute cerebral injury during stroke.

Keywords: ATG7, brain microvascular endothelial cells, ischemia/reperfusion injury, Pro-inflammatory cytokines, Transient focal cerebral ischemia

Received: 19 Sep 2018; Accepted: 05 Nov 2018.

Edited by:

Anna Rosell, Vall d'Hebron Research Institute (VHIR), Spain

Reviewed by:

Bruno Meloni, University of Western Australia, Australia
Abraham Martiin, Achucarro Basque Center for Neuroscience, Spain  

Copyright: © 2018 Wang, Wei, Liu, Zhuang, Li, Liu, Ban, Fang, Cao, Zhao and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Wei-Dong Zhao, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning Province, China, wdzhao@cmu.edu.cn
Prof. Yu-Hua Chen, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning Province, China, yhchen@cmu.edu.cn