Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion
The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB...
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MDPI AG
2020-03-01
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| Series: | International Journal of Molecular Sciences |
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| author | Amelia Nur Vidyanti Jia-Yu Hsieh Kun-Ju Lin Yao-Ching Fang Ismail Setyopranoto Chaur-Jong Hu |
| author_facet | Amelia Nur Vidyanti Jia-Yu Hsieh Kun-Ju Lin Yao-Ching Fang Ismail Setyopranoto Chaur-Jong Hu |
| author_sort | Amelia Nur Vidyanti |
| collection | DOAJ |
| description | The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30−50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI. |
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| id | doaj.art-89a9c822ee5c4cb5b88a455be7c93a06 |
| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T21:46:38Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-89a9c822ee5c4cb5b88a455be7c93a062022-12-22T03:15:36ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-03-01216217610.3390/ijms21062176ijms21062176Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral HypoperfusionAmelia Nur Vidyanti0Jia-Yu Hsieh1Kun-Ju Lin2Yao-Ching Fang3Ismail Setyopranoto4Chaur-Jong Hu5International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Neurology, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Nuclear Medicine and Molecular Imaging Center, Linkou Chang Gung Memorial Hospital, Taoyuan City, 33302, TaiwanTaipei Neuroscience Institute, Taipei 23561, TaiwanDepartment of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, IndonesiaDepartment of Neurology, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanThe pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30−50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.https://www.mdpi.com/1422-0067/21/6/2176vascular cognitive impairmentchronic cerebral hypoperfusionmodified bilateral common carotid artery occlusionhmgb1 |
| spellingShingle | Amelia Nur Vidyanti Jia-Yu Hsieh Kun-Ju Lin Yao-Ching Fang Ismail Setyopranoto Chaur-Jong Hu Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion International Journal of Molecular Sciences vascular cognitive impairment chronic cerebral hypoperfusion modified bilateral common carotid artery occlusion hmgb1 |
| title | Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion |
| title_full | Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion |
| title_fullStr | Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion |
| title_full_unstemmed | Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion |
| title_short | Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion |
| title_sort | role of hmgb1 in an animal model of vascular cognitive impairment induced by chronic cerebral hypoperfusion |
| topic | vascular cognitive impairment chronic cerebral hypoperfusion modified bilateral common carotid artery occlusion hmgb1 |
| url | https://www.mdpi.com/1422-0067/21/6/2176 |
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