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PreprintCited by 15Barrier Structure and Function StudiesNeuroinflammation and Neurodegeneration MechanismsAcute Ischemic Stroke Management

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Integrated transcriptomic and proteomic profiling reveals the key molecular signatures of brain endothelial reperfusion injury

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Ji, Yabin, Chen, Yiman, Tan, Xixi, Huang, Xiaowen, Gao, Qiang, Ma, Yinzhong, Yu, Min, Fang, Cheng, Wang, Yu, Shi, Zhu, Chang, Junlei·2022·CNS Neuroscience & Therapeutics
DOI 10.21203/rs.3.rs-2216319/v1PMC PMC11017417

Preprint — published as 10.1111/cns.14483 · Paper page

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Abstract

Reperfusion after ischemic stroke often causes brain microvascular injury and blood-brain barrier disruption; however, the underlying mechanisms are unclear. Here, we performed transcriptomic and proteomic analyses on human cerebral microvascular endothelial cells following oxygen-glucose deprivation (OGD) or OGD plus recovery (OGD/R), to identify molecules and signaling pathways dysregulated by reperfusion. Transcriptomic analysis identified 390 differentially expressed genes (301 upregulated and 89 downregulated) between the OGD/R and OGD groups. Pathway analysis indicated that the tumor necrosis factor (TNF) signaling pathway was the most significantly enriched. Furthermore, these genes were mostly associated with inflammation, including the TNF signaling pathway, TGF-β signaling pathway, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and NF-κB signaling pathway. On the other hand, 201 differentially expressed proteins (96 upregulated and 105 downregulated) were identified by proteomics between the OGD/R and OGD groups and were primarily associated with extracellular matrix destruction and remodeling, impairment of endothelial transport function, and inflammatory responses. Six genes (DUSP1, JUNB, NFKBIA, NR4A1, SERPINE1, and THBS1) were upregulated by OGD/R at both the mRNA and protein levels. The expression of genes related to inflammatory responses and extracellular matrix were further measured in a mouse model of cerebral ischemia/reperfusion in vivo. Overall, our study provides a comprehensive molecular atlas of brain endothelial reperfusion injury and may facilitate the understanding and treatment of reperfusion injury after ischemic stroke.

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Metadata

Authors
Ji, Y., Chen, Y., Tan, X., Huang, X., Gao, Q., Ma, Y., Yu, M., Fang, C., Wang, Y., Shi, Z., & Chang, J.
Affiliations
  • Chinese Academy of Sciences (CN)
  • University of Hong Kong (HK)
  • Dongguan People’s Hospital (CN)
Corresponding author
  • Shi, Zhu
  • Chang, Junlei
ORCID
Venue
CNS Neuroscience & Therapeutics
Publisher
Springer Science and Business Media LLC
Published
2022-11-02
Volume
30
Issue
4
Pages
e14483-e14483
ISSN
1755-5930 (ISSN-L)
DOI
10.21203/rs.3.rs-2216319/v1
PMC
PMC11017417
OpenAlex
W4387327187
Cited by
15
References
1
Citations by year
2026: 4 · 2025: 8 · 2024: 2 · 2023: 1
FWCI
1.54
Type
journal article
Language
en
Open access
Licence
Locations
  • CNS Neuroscience & Therapeutics (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (2021B1515120089, 32170985)
  • Chinese Academy of Sciences
  • National Key Research and Development Program of China
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
Keywords
ischemia-reperfusion injury, brain microvascular endothelial cells, cerebral ischemia-reperfusion injury, ischemic stroke, oxygen-glucose deprivation, endothelial inflammation, TNF signaling, thrombospondin-1, adalimumab, extracellular matrix remodeling, therapeutic target
MeSH terms
Ischemic Stroke, Animals, Brain, Brain Injuries, Brain Ischemia, Glucose, Humans, Inflammation, Oxygen, Reperfusion, Reperfusion Injury, Gene Expression Profiling, Proteomics, Endothelial Cells, Mice

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