TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
Background Astrocytes regulate blood-brain barrier (BBB) integrity, whereas subarachnoid haemorrhage (SAH) results in astrocyte dysregulation and BBB disruption. Here, we explored the involvement of tissue inhibitor of matrix metalloprotease-1 (TIMP1) in astrocyte-mediated BBB protection during SAH,...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
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| Series: | Stroke and Vascular Neurology |
| Online Access: | https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full |
| _version_ | 1797261953366753280 |
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| author | Jing Liu Huaijun Chen Gao Chen Hang Zhou Cong Qian Tianchi Tang Linfeng Fan Libin Hu Jingya Ye Chaohui Jing Chaoran Xu Xinyan Wu Yike Chen Zihang Chen Xiongjie Fu Jingsen Chen Zhongju Tan Hanhai Zeng Fuyi Liu |
| author_facet | Jing Liu Huaijun Chen Gao Chen Hang Zhou Cong Qian Tianchi Tang Linfeng Fan Libin Hu Jingya Ye Chaohui Jing Chaoran Xu Xinyan Wu Yike Chen Zihang Chen Xiongjie Fu Jingsen Chen Zhongju Tan Hanhai Zeng Fuyi Liu |
| author_sort | Jing Liu |
| collection | DOAJ |
| description | Background Astrocytes regulate blood-brain barrier (BBB) integrity, whereas subarachnoid haemorrhage (SAH) results in astrocyte dysregulation and BBB disruption. Here, we explored the involvement of tissue inhibitor of matrix metalloprotease-1 (TIMP1) in astrocyte-mediated BBB protection during SAH, along with its underlying mechanisms.Methods C57BL/6J mice were used to establish a model of SAH. The effects of TIMP1 on SAH outcomes were analysed by intraperitoneal injection of recombinant mouse TIMP1 protein (rm-TIMP1; 250 µg/kg). The roles of TIMP1 and its effector β1-integrin on astrocytes were observed by in vivo transduction with astrocyte-targeted adeno-associated virus carrying TIMP1 overexpression plasmid or β1-integrin RNAi. The molecular mechanisms underlying TIMP1 and β1-integrin interactions were explored in primary cultured astrocytes stimulated with red blood cells (RBCs).Results TIMP1 was upregulated after SAH. Administration of rm-TIMP1 mitigated SAH-induced early brain injury (EBI) in male and female mice. TIMP1 was primarily expressed in astrocytes; its overexpression in astrocytes led to increased β1-integrin expression in astrocytes, along with the preservation of astrocytic endfoot attachment to the endothelium and subsequent recovery of endothelial tight junctions. All of these effects were reversed by the knockdown of β1-integrin in astrocytes. Molecular analysis showed that TIMP1 overexpression decreased the RBC-induced ubiquitination of β1-integrin; this effect was partially achieved by inhibiting the interaction between β1-integrin and the E3 ubiquitin ligase Trim21.Conclusion TIMP1 inhibits the interaction between β1-integrin and Trim21 in astrocytes, thereby rescuing the ubiquitination of astrocytic β1-integrin. It subsequently restores interactions between astrocytic endfeet and the endothelium, as well as BBB integrity, eventually mitigating SAH-induced EBI. |
| first_indexed | 2024-04-24T23:49:24Z |
| format | Article |
| id | doaj.art-118347a0ddfc4b5a8df707e955635b5d |
| institution | Directory Open Access Journal |
| issn | 2059-8696 |
| language | English |
| last_indexed | 2024-04-24T23:49:24Z |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Stroke and Vascular Neurology |
| spelling | doaj.art-118347a0ddfc4b5a8df707e955635b5d2024-03-14T18:10:09ZengBMJ Publishing GroupStroke and Vascular Neurology2059-869610.1136/svn-2023-002956TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrinJing Liu0Huaijun Chen1Gao Chen2Hang Zhou3Cong Qian4Tianchi Tang5Linfeng Fan6Libin Hu7Jingya Ye8Chaohui Jing9Chaoran Xu10Xinyan Wu11Yike Chen12Zihang Chen13Xiongjie Fu14Jingsen Chen15Zhongju Tan16Hanhai Zeng17Fuyi Liu18Department of Nursing, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China4 People’s Hospital of Deyang City, Deyang, ChinaKey Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, ChinastatisticianDepartment of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaDepartment of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaZhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaShanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaKey Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaZhejiang University School of Medicine First Affiliated Hospital, Hangzhou, Zhejiang, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaNeurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, ChinaBackground Astrocytes regulate blood-brain barrier (BBB) integrity, whereas subarachnoid haemorrhage (SAH) results in astrocyte dysregulation and BBB disruption. Here, we explored the involvement of tissue inhibitor of matrix metalloprotease-1 (TIMP1) in astrocyte-mediated BBB protection during SAH, along with its underlying mechanisms.Methods C57BL/6J mice were used to establish a model of SAH. The effects of TIMP1 on SAH outcomes were analysed by intraperitoneal injection of recombinant mouse TIMP1 protein (rm-TIMP1; 250 µg/kg). The roles of TIMP1 and its effector β1-integrin on astrocytes were observed by in vivo transduction with astrocyte-targeted adeno-associated virus carrying TIMP1 overexpression plasmid or β1-integrin RNAi. The molecular mechanisms underlying TIMP1 and β1-integrin interactions were explored in primary cultured astrocytes stimulated with red blood cells (RBCs).Results TIMP1 was upregulated after SAH. Administration of rm-TIMP1 mitigated SAH-induced early brain injury (EBI) in male and female mice. TIMP1 was primarily expressed in astrocytes; its overexpression in astrocytes led to increased β1-integrin expression in astrocytes, along with the preservation of astrocytic endfoot attachment to the endothelium and subsequent recovery of endothelial tight junctions. All of these effects were reversed by the knockdown of β1-integrin in astrocytes. Molecular analysis showed that TIMP1 overexpression decreased the RBC-induced ubiquitination of β1-integrin; this effect was partially achieved by inhibiting the interaction between β1-integrin and the E3 ubiquitin ligase Trim21.Conclusion TIMP1 inhibits the interaction between β1-integrin and Trim21 in astrocytes, thereby rescuing the ubiquitination of astrocytic β1-integrin. It subsequently restores interactions between astrocytic endfeet and the endothelium, as well as BBB integrity, eventually mitigating SAH-induced EBI.https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full |
| spellingShingle | Jing Liu Huaijun Chen Gao Chen Hang Zhou Cong Qian Tianchi Tang Linfeng Fan Libin Hu Jingya Ye Chaohui Jing Chaoran Xu Xinyan Wu Yike Chen Zihang Chen Xiongjie Fu Jingsen Chen Zhongju Tan Hanhai Zeng Fuyi Liu TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin Stroke and Vascular Neurology |
| title | TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin |
| title_full | TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin |
| title_fullStr | TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin |
| title_full_unstemmed | TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin |
| title_short | TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin |
| title_sort | timp1 protects against blood brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1 integrin |
| url | https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full |
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