Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation
Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythr...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-07-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323171830140X |
| _version_ | 1818173999265349632 |
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| author | Tuo Yang Yang Sun Leilei Mao Meijuan Zhang Qianqian Li Lili Zhang Yejie Shi Rehana K. Leak Jun Chen Feng Zhang |
| author_facet | Tuo Yang Yang Sun Leilei Mao Meijuan Zhang Qianqian Li Lili Zhang Yejie Shi Rehana K. Leak Jun Chen Feng Zhang |
| author_sort | Tuo Yang |
| collection | DOAJ |
| description | Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation. Keywords: Stroke, Neuroprotection, Ischemic tolerance, Electrophile, Lipid peroxidation, VE-cadherin, Conditioning |
| first_indexed | 2024-12-11T19:37:25Z |
| format | Article |
| id | doaj.art-855c95a43f974b4c9ddc4c01cb084ead |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-11T19:37:25Z |
| publishDate | 2018-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-855c95a43f974b4c9ddc4c01cb084ead2022-12-22T00:53:06ZengElsevierRedox Biology2213-23172018-07-0117323337Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activationTuo Yang0Yang Sun1Leilei Mao2Meijuan Zhang3Qianqian Li4Lili Zhang5Yejie Shi6Rehana K. Leak7Jun Chen8Feng Zhang9Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USADepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USADepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology and Key Laboratory of Cerebral Microcirculation, University of Shandong, Affiliated Hospital of Taishan Medical College, Tai’an, Shandong, ChinaDepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, ChinaDepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USADepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USADepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USAGraduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USADepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USADepartment of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology and Key Laboratory of Cerebral Microcirculation, University of Shandong, Affiliated Hospital of Taishan Medical College, Tai’an, Shandong, China; Corresponding author at: Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA.Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation. Keywords: Stroke, Neuroprotection, Ischemic tolerance, Electrophile, Lipid peroxidation, VE-cadherin, Conditioninghttp://www.sciencedirect.com/science/article/pii/S221323171830140X |
| spellingShingle | Tuo Yang Yang Sun Leilei Mao Meijuan Zhang Qianqian Li Lili Zhang Yejie Shi Rehana K. Leak Jun Chen Feng Zhang Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation Redox Biology |
| title | Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation |
| title_full | Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation |
| title_fullStr | Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation |
| title_full_unstemmed | Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation |
| title_short | Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation |
| title_sort | brain ischemic preconditioning protects against ischemic injury and preserves the blood brain barrier via oxidative signaling and nrf2 activation |
| url | http://www.sciencedirect.com/science/article/pii/S221323171830140X |
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