ArticleStroke and vascular neurology2024
TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin.
Article in Stroke and vascular neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 15 citations in OpenAlex.
- Astrocytes in Multiple Sclerosis: Getting to the Core.International journal of molecular sciences · 2026Review
- Endothelialized human umbilical cord mesenchymal stem cell-derived exosomes enhances angiogenesis and stabilizes the blood-spinal cord barrier after spinal cord injury.Journal of nanobiotechnology · 2026Article
- Alisol A Mitigates Neuroinflammation and Oxidative Stress After Subarachnoid Hemorrhage Through SIRT3-Driven Reprogramming of Mitochondrial Metabolism.Molecular neurobiology · 2026Article
- Implantation of human mesenchymal stromal cell pellet for therapeutic angiogenesis.Cytotherapy · 2026Article
- TRIM21 Exacerbates Ischemic Brain Injury by Promoting Astrocyte-Mediated Neuroinflammation via K63-Linked Ubiquitination of MDA5.Research (Washington, D.C.) · 2026Article
- Identification of TIMP1 as a Key Regulator of Ferroptosis in Ulcerative Colitis Through Bioinformatics and Functional Experiments.Gastroenterology research and practice · 2026Article
- Selective Deletion of NBCe1 in Reactive Astrocytes Attenuates Ischemic Stroke Brain Damage.Glia · 2025Article
- Identification of post-translational modification-related biomarkers in ischemic stroke using bioinformatics and machine learning.Scientific reports · 2025Article
- Synergistic Neuroprotection of Artesunate and Tetramethylpyrazine in Ischemic Stroke, Mechanisms of Blood-Brain Barrier Preservation.International journal of molecular sciences · 2025Article
- TIMP1 promotes microglia M2 polarization through MAPK pathway to ameliorate early brain injury after ischemia.Hereditas · 2025Article
- Ubiquitination-mediated protein homeostasis in cardiovascular diseases: molecular mechanisms and therapeutic opportunities.American journal of cardiovascular disease · 2025Review
- Tenascin-C Facilitates Microglial Polarization via TLR4/MyD88/NF-κB Pathway Following Subarachnoid Hemorrhage.Journal of inflammation research · 2025Article
- TIMP1 regulates ferroptosis in osteoblasts by inhibiting TFRC ubiquitination: an in vitro and in vivo study.Molecular medicine (Cambridge, Mass.) · 2024Article
- Inflammation-Derived and Clinical Indicator-Based Predictive Model for Ischemic Stroke Recovery.Journal of the American Heart Association · 2024Article
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19 authors at 4 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundAstrocytes 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.
methodsC57BL/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).
resultsTIMP1 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.
conclusionTIMP1 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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