Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain
Abstract Background Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates vascular extracellular matrix composition and matrix metalloproteinase (MMP) activity. The blood-brain barrier (BBB) is a dynamic system assembled by endothelial cells, basal lamina, and peri...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-017-1032-1 |
| _version_ | 1819151214165622784 |
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| author | Marina S. Hernandes Bernard Lassègue Lula L. Hilenski Jonathan Adams Ning Gao Chia-Yi Kuan Yu-Yo Sun Lihong Cheng Daniel S. Kikuchi Manuel Yepes Kathy K. Griendling |
| author_facet | Marina S. Hernandes Bernard Lassègue Lula L. Hilenski Jonathan Adams Ning Gao Chia-Yi Kuan Yu-Yo Sun Lihong Cheng Daniel S. Kikuchi Manuel Yepes Kathy K. Griendling |
| author_sort | Marina S. Hernandes |
| collection | DOAJ |
| description | Abstract Background Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates vascular extracellular matrix composition and matrix metalloproteinase (MMP) activity. The blood-brain barrier (BBB) is a dynamic system assembled by endothelial cells, basal lamina, and perivascular astrocytes, raising the possibility that Poldip2 may be involved in maintaining its structure. We investigated the role of Poldip2 in the late BBB permeability induced by cerebral ischemia. Methods Transient middle cerebral artery occlusion (tMCAO) was induced in Poldip2+/+ and Poldip2+/− mice. The volume of the ischemic lesion was measured in triphenyltetrazolium chloride-stained sections. BBB breakdown was evaluated by Evans blue dye extravasation. Poldip2 protein expression was evaluated by western blotting. RT-PCR, zymography, and ELISAs were used to measure mRNA levels, activity, and protein levels of cytokines and MMPs. Cultured astrocytes were transfected with Poldip2 siRNA, and mRNA levels of cytokines were evaluated as well as IκBα protein degradation. Results Cerebral ischemia induced the expression of Poldip2. Compared to Poldip2+/+ mice, Poldip2+/− animals exhibited decreased Evans blue dye extravasation and improved survival 24 h following stroke. Poldip2 expression was upregulated in astrocytes exposed to oxygen and glucose deprivation (OGD) and siRNA-mediated downregulation of Poldip2 abrogated OGD-induced IL-6 and TNF-α expression. In addition, siRNA against Poldip2 inhibited TNF-α-induced IκBα degradation. TNF-α, IL-6, MCP-1, VEGF, and MMP expression induced by cerebral ischemia was abrogated in Poldip2+/− mice. The protective effect of Poldip2 depletion on the increased permeability of the BBB was partially reversed by systemic administration of TNF-α. Conclusions Poldip2 is upregulated following ischemic stroke and mediates the breakdown of the BBB by increasing cerebral cytokine production and MMP activation. Therefore, Poldip2 appears to be a promising novel target for the development of therapeutic strategies to prevent the development of cerebral edema in the ischemic brain. |
| first_indexed | 2024-12-22T14:29:50Z |
| format | Article |
| id | doaj.art-549f9309bf8a4a48b1dd21f638a4ca90 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-22T14:29:50Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-549f9309bf8a4a48b1dd21f638a4ca902022-12-21T18:22:47ZengBMCJournal of Neuroinflammation1742-20942018-02-0115111610.1186/s12974-017-1032-1Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brainMarina S. Hernandes0Bernard Lassègue1Lula L. Hilenski2Jonathan Adams3Ning Gao4Chia-Yi Kuan5Yu-Yo Sun6Lihong Cheng7Daniel S. Kikuchi8Manuel Yepes9Kathy K. Griendling10Division of Cardiology, Department of Medicine, Emory UniversityDivision of Cardiology, Department of Medicine, Emory UniversityDivision of Cardiology, Department of Medicine, Emory UniversityDivision of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory UniversityDivision of Neurology, Department of Pediatrics, Emory UniversityDivision of Neurology, Department of Pediatrics, Emory UniversityDivision of Neurology, Department of Pediatrics, Emory UniversityDepartment of Neurology, Emory UniversityDivision of Cardiology, Department of Medicine, Emory UniversityDepartment of Neurology, Emory UniversityDivision of Cardiology, Department of Medicine, Emory UniversityAbstract Background Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates vascular extracellular matrix composition and matrix metalloproteinase (MMP) activity. The blood-brain barrier (BBB) is a dynamic system assembled by endothelial cells, basal lamina, and perivascular astrocytes, raising the possibility that Poldip2 may be involved in maintaining its structure. We investigated the role of Poldip2 in the late BBB permeability induced by cerebral ischemia. Methods Transient middle cerebral artery occlusion (tMCAO) was induced in Poldip2+/+ and Poldip2+/− mice. The volume of the ischemic lesion was measured in triphenyltetrazolium chloride-stained sections. BBB breakdown was evaluated by Evans blue dye extravasation. Poldip2 protein expression was evaluated by western blotting. RT-PCR, zymography, and ELISAs were used to measure mRNA levels, activity, and protein levels of cytokines and MMPs. Cultured astrocytes were transfected with Poldip2 siRNA, and mRNA levels of cytokines were evaluated as well as IκBα protein degradation. Results Cerebral ischemia induced the expression of Poldip2. Compared to Poldip2+/+ mice, Poldip2+/− animals exhibited decreased Evans blue dye extravasation and improved survival 24 h following stroke. Poldip2 expression was upregulated in astrocytes exposed to oxygen and glucose deprivation (OGD) and siRNA-mediated downregulation of Poldip2 abrogated OGD-induced IL-6 and TNF-α expression. In addition, siRNA against Poldip2 inhibited TNF-α-induced IκBα degradation. TNF-α, IL-6, MCP-1, VEGF, and MMP expression induced by cerebral ischemia was abrogated in Poldip2+/− mice. The protective effect of Poldip2 depletion on the increased permeability of the BBB was partially reversed by systemic administration of TNF-α. Conclusions Poldip2 is upregulated following ischemic stroke and mediates the breakdown of the BBB by increasing cerebral cytokine production and MMP activation. Therefore, Poldip2 appears to be a promising novel target for the development of therapeutic strategies to prevent the development of cerebral edema in the ischemic brain.http://link.springer.com/article/10.1186/s12974-017-1032-1Poldip2Cerebral ischemiaBlood-brain barrierCytokinesAstrocytes |
| spellingShingle | Marina S. Hernandes Bernard Lassègue Lula L. Hilenski Jonathan Adams Ning Gao Chia-Yi Kuan Yu-Yo Sun Lihong Cheng Daniel S. Kikuchi Manuel Yepes Kathy K. Griendling Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain Journal of Neuroinflammation Poldip2 Cerebral ischemia Blood-brain barrier Cytokines Astrocytes |
| title | Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain |
| title_full | Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain |
| title_fullStr | Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain |
| title_full_unstemmed | Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain |
| title_short | Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain |
| title_sort | polymerase delta interacting protein 2 deficiency protects against blood brain barrier permeability in the ischemic brain |
| topic | Poldip2 Cerebral ischemia Blood-brain barrier Cytokines Astrocytes |
| url | http://link.springer.com/article/10.1186/s12974-017-1032-1 |
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