Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis
Abstract Hypoxia–reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheime...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2020-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03293-0 |
| _version_ | 1818844680991801344 |
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| author | Young-Sun Lee Ji-Young Choi Sakulrat Mankhong Sohee Moon Sujin Kim Young Ho Koh Ji-Hye Kim Ju-Hee Kang |
| author_facet | Young-Sun Lee Ji-Young Choi Sakulrat Mankhong Sohee Moon Sujin Kim Young Ho Koh Ji-Hye Kim Ju-Hee Kang |
| author_sort | Young-Sun Lee |
| collection | DOAJ |
| description | Abstract Hypoxia–reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheimer’s disease (AD) pathologies. Therefore, we investigated the roles of hypoxia–reoxygenation (H/R)-induced release of high mobility group box protein 1 (HMGB1), a risk molecule for AD pathogenesis in the ischaemic damaged brain, from human brain microvascular endothelial cells (HBMVECs) in neuronal amyloid-beta (Aβ) production. H/R increased nuclear–cytosolic translocation and secretion of HMGB1 in HBMVECs, along with increased permeability and HMGB1-dependent p-c-Jun activation. In addition, H/R increased the expression of Sirtuin 1 (Sirt1), coincident with an increase of intracellular Sirt1–HMGB1 binding in HBMVECs. H/R increased the acetylation of HMGB1 and extracellular secretion, which was significantly inhibited by Sirt1 overexpression. Furthermore, Sirt1 contributed to autophagy-mediated endogenous HMGB1 degradation. More importantly, treatment of neuronal cells with conditioned medium from H/R-stimulated HBMVECs (H/R-CM) activated their amyloidogenic pathways. The neuronal amyloidogenic changes (i.e. increased levels of extracellular Aβ40 and Aβ42) by H/R-CM from HBMVECs were further increased by Sirt1 inhibition, which was significantly suppressed by neutralization of the HMGB1 in H/R-CM. Collectively, our results suggest that HMGB1 derived from H/R-stimulated HBMVECs contributes to amyloidogenic pathways in neurons playing roles in the pathogenesis of AD, which are regulated by endothelial Sirt1. |
| first_indexed | 2024-12-19T05:17:37Z |
| format | Article |
| id | doaj.art-294d891d25da45cf9d9978b9333d3ad3 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-19T05:17:37Z |
| publishDate | 2020-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-294d891d25da45cf9d9978b9333d3ad32022-12-21T20:34:37ZengNature Publishing GroupCell Death and Disease2041-48892020-12-01111211210.1038/s41419-020-03293-0Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesisYoung-Sun Lee0Ji-Young Choi1Sakulrat Mankhong2Sohee Moon3Sujin Kim4Young Ho Koh5Ji-Hye Kim6Ju-Hee Kang7Department of Pharmacology, College of Medicine, Inha UniversityDivision of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of HealthDepartment of Pharmacology, College of Medicine, Inha UniversityDepartment of Pharmacology, College of Medicine, Inha UniversityDepartment of Pharmacology, College of Medicine, Inha UniversityDivision of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of HealthDepartment of Emergency Medicine, Inha University HospitalDepartment of Pharmacology, College of Medicine, Inha UniversityAbstract Hypoxia–reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheimer’s disease (AD) pathologies. Therefore, we investigated the roles of hypoxia–reoxygenation (H/R)-induced release of high mobility group box protein 1 (HMGB1), a risk molecule for AD pathogenesis in the ischaemic damaged brain, from human brain microvascular endothelial cells (HBMVECs) in neuronal amyloid-beta (Aβ) production. H/R increased nuclear–cytosolic translocation and secretion of HMGB1 in HBMVECs, along with increased permeability and HMGB1-dependent p-c-Jun activation. In addition, H/R increased the expression of Sirtuin 1 (Sirt1), coincident with an increase of intracellular Sirt1–HMGB1 binding in HBMVECs. H/R increased the acetylation of HMGB1 and extracellular secretion, which was significantly inhibited by Sirt1 overexpression. Furthermore, Sirt1 contributed to autophagy-mediated endogenous HMGB1 degradation. More importantly, treatment of neuronal cells with conditioned medium from H/R-stimulated HBMVECs (H/R-CM) activated their amyloidogenic pathways. The neuronal amyloidogenic changes (i.e. increased levels of extracellular Aβ40 and Aβ42) by H/R-CM from HBMVECs were further increased by Sirt1 inhibition, which was significantly suppressed by neutralization of the HMGB1 in H/R-CM. Collectively, our results suggest that HMGB1 derived from H/R-stimulated HBMVECs contributes to amyloidogenic pathways in neurons playing roles in the pathogenesis of AD, which are regulated by endothelial Sirt1.https://doi.org/10.1038/s41419-020-03293-0 |
| spellingShingle | Young-Sun Lee Ji-Young Choi Sakulrat Mankhong Sohee Moon Sujin Kim Young Ho Koh Ji-Hye Kim Ju-Hee Kang Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis Cell Death and Disease |
| title | Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis |
| title_full | Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis |
| title_fullStr | Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis |
| title_full_unstemmed | Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis |
| title_short | Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia–reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis |
| title_sort | sirtuin 1 dependent regulation of high mobility box 1 in hypoxia reoxygenated brain microvascular endothelial cells roles in neuronal amyloidogenesis |
| url | https://doi.org/10.1038/s41419-020-03293-0 |
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