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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Autor*in:	Jing Liu [verfasserIn] Huaijun Chen [verfasserIn] Gao Chen [verfasserIn] Hang Zhou [verfasserIn] Cong Qian [verfasserIn] Tianchi Tang [verfasserIn] Linfeng Fan [verfasserIn] Libin Hu [verfasserIn] Jingya Ye [verfasserIn] Chaohui Jing [verfasserIn] Chaoran Xu [verfasserIn] Xinyan Wu [verfasserIn] Yike Chen [verfasserIn] Zihang Chen [verfasserIn] Xiongjie Fu [verfasserIn] Jingsen Chen [verfasserIn] Zhongju Tan [verfasserIn] Hanhai Zeng [verfasserIn] Fuyi Liu [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Übergeordnetes Werk:	In: Stroke and Vascular Neurology - BMJ Publishing Group, 2018

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1136/svn-2023-002956

Katalog-ID:	DOAJ097192422

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520			\|a 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.
653		0	\|a Neurology. Diseases of the nervous system
700	0		\|a Huaijun Chen \|e verfasserin \|4 aut
700	0		\|a Gao Chen \|e verfasserin \|4 aut
700	0		\|a Hang Zhou \|e verfasserin \|4 aut
700	0		\|a Cong Qian \|e verfasserin \|4 aut
700	0		\|a Tianchi Tang \|e verfasserin \|4 aut
700	0		\|a Linfeng Fan \|e verfasserin \|4 aut
700	0		\|a Libin Hu \|e verfasserin \|4 aut
700	0		\|a Jingya Ye \|e verfasserin \|4 aut
700	0		\|a Chaohui Jing \|e verfasserin \|4 aut
700	0		\|a Chaoran Xu \|e verfasserin \|4 aut
700	0		\|a Xinyan Wu \|e verfasserin \|4 aut
700	0		\|a Yike Chen \|e verfasserin \|4 aut
700	0		\|a Zihang Chen \|e verfasserin \|4 aut
700	0		\|a Xiongjie Fu \|e verfasserin \|4 aut
700	0		\|a Jingsen Chen \|e verfasserin \|4 aut
700	0		\|a Zhongju Tan \|e verfasserin \|4 aut
700	0		\|a Hanhai Zeng \|e verfasserin \|4 aut
700	0		\|a Fuyi Liu \|e verfasserin \|4 aut
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allfields	10.1136/svn-2023-002956 doi (DE-627)DOAJ097192422 (DE-599)DOAJ118347a0ddfc4b5a8df707e955635b5d DE-627 ger DE-627 rakwb eng RC346-429 Jing Liu verfasserin aut TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neurology. Diseases of the nervous system Huaijun Chen verfasserin aut Gao Chen verfasserin aut Hang Zhou verfasserin aut Cong Qian verfasserin aut Tianchi Tang verfasserin aut Linfeng Fan verfasserin aut Libin Hu verfasserin aut Jingya Ye verfasserin aut Chaohui Jing verfasserin aut Chaoran Xu verfasserin aut Xinyan Wu verfasserin aut Yike Chen verfasserin aut Zihang Chen verfasserin aut Xiongjie Fu verfasserin aut Jingsen Chen verfasserin aut Zhongju Tan verfasserin aut Hanhai Zeng verfasserin aut Fuyi Liu verfasserin aut In Stroke and Vascular Neurology BMJ Publishing Group, 2018 (DE-627)848316193 (DE-600)2847692-X 20598696 nnns https://doi.org/10.1136/svn-2023-002956 kostenfrei https://doaj.org/article/118347a0ddfc4b5a8df707e955635b5d kostenfrei https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full kostenfrei https://doaj.org/toc/2059-8696 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ AR
spelling	10.1136/svn-2023-002956 doi (DE-627)DOAJ097192422 (DE-599)DOAJ118347a0ddfc4b5a8df707e955635b5d DE-627 ger DE-627 rakwb eng RC346-429 Jing Liu verfasserin aut TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neurology. Diseases of the nervous system Huaijun Chen verfasserin aut Gao Chen verfasserin aut Hang Zhou verfasserin aut Cong Qian verfasserin aut Tianchi Tang verfasserin aut Linfeng Fan verfasserin aut Libin Hu verfasserin aut Jingya Ye verfasserin aut Chaohui Jing verfasserin aut Chaoran Xu verfasserin aut Xinyan Wu verfasserin aut Yike Chen verfasserin aut Zihang Chen verfasserin aut Xiongjie Fu verfasserin aut Jingsen Chen verfasserin aut Zhongju Tan verfasserin aut Hanhai Zeng verfasserin aut Fuyi Liu verfasserin aut In Stroke and Vascular Neurology BMJ Publishing Group, 2018 (DE-627)848316193 (DE-600)2847692-X 20598696 nnns https://doi.org/10.1136/svn-2023-002956 kostenfrei https://doaj.org/article/118347a0ddfc4b5a8df707e955635b5d kostenfrei https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full kostenfrei https://doaj.org/toc/2059-8696 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ AR
allfields_unstemmed	10.1136/svn-2023-002956 doi (DE-627)DOAJ097192422 (DE-599)DOAJ118347a0ddfc4b5a8df707e955635b5d DE-627 ger DE-627 rakwb eng RC346-429 Jing Liu verfasserin aut TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neurology. Diseases of the nervous system Huaijun Chen verfasserin aut Gao Chen verfasserin aut Hang Zhou verfasserin aut Cong Qian verfasserin aut Tianchi Tang verfasserin aut Linfeng Fan verfasserin aut Libin Hu verfasserin aut Jingya Ye verfasserin aut Chaohui Jing verfasserin aut Chaoran Xu verfasserin aut Xinyan Wu verfasserin aut Yike Chen verfasserin aut Zihang Chen verfasserin aut Xiongjie Fu verfasserin aut Jingsen Chen verfasserin aut Zhongju Tan verfasserin aut Hanhai Zeng verfasserin aut Fuyi Liu verfasserin aut In Stroke and Vascular Neurology BMJ Publishing Group, 2018 (DE-627)848316193 (DE-600)2847692-X 20598696 nnns https://doi.org/10.1136/svn-2023-002956 kostenfrei https://doaj.org/article/118347a0ddfc4b5a8df707e955635b5d kostenfrei https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full kostenfrei https://doaj.org/toc/2059-8696 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ AR
allfieldsGer	10.1136/svn-2023-002956 doi (DE-627)DOAJ097192422 (DE-599)DOAJ118347a0ddfc4b5a8df707e955635b5d DE-627 ger DE-627 rakwb eng RC346-429 Jing Liu verfasserin aut TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neurology. Diseases of the nervous system Huaijun Chen verfasserin aut Gao Chen verfasserin aut Hang Zhou verfasserin aut Cong Qian verfasserin aut Tianchi Tang verfasserin aut Linfeng Fan verfasserin aut Libin Hu verfasserin aut Jingya Ye verfasserin aut Chaohui Jing verfasserin aut Chaoran Xu verfasserin aut Xinyan Wu verfasserin aut Yike Chen verfasserin aut Zihang Chen verfasserin aut Xiongjie Fu verfasserin aut Jingsen Chen verfasserin aut Zhongju Tan verfasserin aut Hanhai Zeng verfasserin aut Fuyi Liu verfasserin aut In Stroke and Vascular Neurology BMJ Publishing Group, 2018 (DE-627)848316193 (DE-600)2847692-X 20598696 nnns https://doi.org/10.1136/svn-2023-002956 kostenfrei https://doaj.org/article/118347a0ddfc4b5a8df707e955635b5d kostenfrei https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full kostenfrei https://doaj.org/toc/2059-8696 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ AR
allfieldsSound	10.1136/svn-2023-002956 doi (DE-627)DOAJ097192422 (DE-599)DOAJ118347a0ddfc4b5a8df707e955635b5d DE-627 ger DE-627 rakwb eng RC346-429 Jing Liu verfasserin aut TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neurology. Diseases of the nervous system Huaijun Chen verfasserin aut Gao Chen verfasserin aut Hang Zhou verfasserin aut Cong Qian verfasserin aut Tianchi Tang verfasserin aut Linfeng Fan verfasserin aut Libin Hu verfasserin aut Jingya Ye verfasserin aut Chaohui Jing verfasserin aut Chaoran Xu verfasserin aut Xinyan Wu verfasserin aut Yike Chen verfasserin aut Zihang Chen verfasserin aut Xiongjie Fu verfasserin aut Jingsen Chen verfasserin aut Zhongju Tan verfasserin aut Hanhai Zeng verfasserin aut Fuyi Liu verfasserin aut In Stroke and Vascular Neurology BMJ Publishing Group, 2018 (DE-627)848316193 (DE-600)2847692-X 20598696 nnns https://doi.org/10.1136/svn-2023-002956 kostenfrei https://doaj.org/article/118347a0ddfc4b5a8df707e955635b5d kostenfrei https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full kostenfrei https://doaj.org/toc/2059-8696 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ AR
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authorswithroles_txt_mv	Jing Liu @@aut@@ Huaijun Chen @@aut@@ Gao Chen @@aut@@ Hang Zhou @@aut@@ Cong Qian @@aut@@ Tianchi Tang @@aut@@ Linfeng Fan @@aut@@ Libin Hu @@aut@@ Jingya Ye @@aut@@ Chaohui Jing @@aut@@ Chaoran Xu @@aut@@ Xinyan Wu @@aut@@ Yike Chen @@aut@@ Zihang Chen @@aut@@ Xiongjie Fu @@aut@@ Jingsen Chen @@aut@@ Zhongju Tan @@aut@@ Hanhai Zeng @@aut@@ Fuyi Liu @@aut@@
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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.</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neurology. 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callnumber-first	R - Medicine
author	Jing Liu
spellingShingle	Jing Liu misc RC346-429 misc Neurology. Diseases of the nervous system TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
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topic_title	RC346-429 TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
topic	misc RC346-429 misc Neurology. Diseases of the nervous system
topic_unstemmed	misc RC346-429 misc Neurology. Diseases of the nervous system
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title	TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
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title_full	TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
author_sort	Jing Liu
journal	Stroke and Vascular Neurology
journalStr	Stroke and Vascular Neurology
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author_browse	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
class	RC346-429
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title_sort	timp1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
callnumber	RC346-429
title_auth	TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin
url	https://doi.org/10.1136/svn-2023-002956 https://doaj.org/article/118347a0ddfc4b5a8df707e955635b5d https://svn.bmj.com/content/early/2024/03/14/svn-2023-002956.full https://doaj.org/toc/2059-8696
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author2	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
author2Str	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
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up_date	2024-07-04T00:10:23.588Z
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