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Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke
Ischemic stroke can cause blood-brain barrier (BBB) injury, which worsens brain damage induced by stroke. Abnormal expression of tight junction proteins in endothelial cells (ECs) can increase intracellular space and BBB leakage. Selective inhibition of mitogen-activated protein kinase, the negative...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer - Medknow
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154501/ https://www.ncbi.nlm.nih.gov/pubmed/36751800 http://dx.doi.org/10.4103/1673-5374.363836 |
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author | Qin, Xiu-De Yang, Tai-Qin Zeng, Jing-Hui Cai, Hao-Bin Qi, Shao-Hua Jiang, Jian-Jun Cheng, Ying Xu, Long-Sheng Bu, Fan |
author_facet | Qin, Xiu-De Yang, Tai-Qin Zeng, Jing-Hui Cai, Hao-Bin Qi, Shao-Hua Jiang, Jian-Jun Cheng, Ying Xu, Long-Sheng Bu, Fan |
author_sort | Qin, Xiu-De |
collection | PubMed |
description | Ischemic stroke can cause blood-brain barrier (BBB) injury, which worsens brain damage induced by stroke. Abnormal expression of tight junction proteins in endothelial cells (ECs) can increase intracellular space and BBB leakage. Selective inhibition of mitogen-activated protein kinase, the negative regulatory substrate of mitogen-activated protein kinase phosphatase (MKP)-1, improves tight junction protein function in ECs, and genetic deletion of MKP-1 aggravates ischemic brain injury. However, whether the latter affects BBB integrity, and the cell type-specific mechanism underlying this process, remain unclear. In this study, we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke. We found that overexpression of MKP-1 in ECs reduced infarct volume, reduced the level of inflammatory factors interleukin-1β, interleukin-6, and chemokine C-C motif ligand-2, inhibited vascular injury, and promoted the recovery of sensorimotor and memory/cognitive function. Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase (ERK) 1/2 and the downregulation of occludin expression. Finally, to investigate the mechanism by which MKP-1 exerted these functions in ECs, we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose, and pharmacologically inhibited the activity of MKP-1 and ERK1/2. Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death, cell monolayer leakage, and downregulation of occludin expression, and that inhibiting ERK1/2 can reverse these effects. In addition, co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2. These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2, thereby protecting the integrity of BBB, alleviating brain injury, and improving post-stroke prognosis. |
format | Online Article Text |
id | pubmed-10154501 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Wolters Kluwer - Medknow |
record_format | MEDLINE/PubMed |
spelling | pubmed-101545012023-05-04 Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke Qin, Xiu-De Yang, Tai-Qin Zeng, Jing-Hui Cai, Hao-Bin Qi, Shao-Hua Jiang, Jian-Jun Cheng, Ying Xu, Long-Sheng Bu, Fan Neural Regen Res Research Article Ischemic stroke can cause blood-brain barrier (BBB) injury, which worsens brain damage induced by stroke. Abnormal expression of tight junction proteins in endothelial cells (ECs) can increase intracellular space and BBB leakage. Selective inhibition of mitogen-activated protein kinase, the negative regulatory substrate of mitogen-activated protein kinase phosphatase (MKP)-1, improves tight junction protein function in ECs, and genetic deletion of MKP-1 aggravates ischemic brain injury. However, whether the latter affects BBB integrity, and the cell type-specific mechanism underlying this process, remain unclear. In this study, we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke. We found that overexpression of MKP-1 in ECs reduced infarct volume, reduced the level of inflammatory factors interleukin-1β, interleukin-6, and chemokine C-C motif ligand-2, inhibited vascular injury, and promoted the recovery of sensorimotor and memory/cognitive function. Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase (ERK) 1/2 and the downregulation of occludin expression. Finally, to investigate the mechanism by which MKP-1 exerted these functions in ECs, we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose, and pharmacologically inhibited the activity of MKP-1 and ERK1/2. Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death, cell monolayer leakage, and downregulation of occludin expression, and that inhibiting ERK1/2 can reverse these effects. In addition, co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2. These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2, thereby protecting the integrity of BBB, alleviating brain injury, and improving post-stroke prognosis. Wolters Kluwer - Medknow 2023-01-05 /pmc/articles/PMC10154501/ /pubmed/36751800 http://dx.doi.org/10.4103/1673-5374.363836 Text en Copyright: © Neural Regeneration Research https://creativecommons.org/licenses/by-nc-sa/4.0/This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. |
spellingShingle | Research Article Qin, Xiu-De Yang, Tai-Qin Zeng, Jing-Hui Cai, Hao-Bin Qi, Shao-Hua Jiang, Jian-Jun Cheng, Ying Xu, Long-Sheng Bu, Fan Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke |
title | Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke |
title_full | Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke |
title_fullStr | Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke |
title_full_unstemmed | Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke |
title_short | Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke |
title_sort | overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154501/ https://www.ncbi.nlm.nih.gov/pubmed/36751800 http://dx.doi.org/10.4103/1673-5374.363836 |
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