Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat
Abstract
Matrix metalloproteinases (MMPs) disrupt the blood-brain barrier (BBB) during reperfusion. Occludin and claudins are recently described tight junction proteins (TJPs) that form the BBB. We hypothesized that the opening of the BBB was because of the degradation of TJPs by the MMPs. Spontaneously hypertensive rats had a 90 mins middle cerebral artery occlusion with reperfusion for 2, 3, or 24 h. Matrix metalloproteinases were measured by immunohistochemistry and in situ and gel zymography. Real-time polymerase chain reaction (PCR) measured mRNAs of MMP-2 and -9, furin, membrane-type MMP (MT1-MMP), occludin, and claudin-5. There was opening of the BBB in the piriform cortex after 3 h of reperfusion, and an MMP inhibitor, BB-1101 (30 mg/kg), prevented the opening. At 3 h, in situ zymograms showed gelatinase activity. Zymography and PCR showed greater increases in MMP-2 than in MMP-9. There were increased mRNA and immunohistochemistry for MT1-MMP and furin, which activate MMP-2. Claudin-5 and occludin mRNA expression decreased at 2 h in both hemispheres with fragments of both proteins seen on Western blot by 3 h on the ischemic side; treatment with BB-1101 reversed the degradation of the TJPs. Immunohistochemistry at 3 h showed fragmented TJPs within the endothelial cell clefts. By 24 h, in situ zymography showed gelatinase activity and gel zymography showed elevated levels of MMP-9. Disrupted TJPs previously seen in endothelial cells appeared in the surrounding astrocytes. Our results provide direct evidence that MMPs open the BBB by degrading TJPs and that an MMP inhibitor prevents degradation of the TJPs by MMPs.
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The complex signaling pathway at the blood/CNS interface is constituted by the sequence of selectins, chemokines and integrins, resulting in emperipolesis through matrix metalloproteinases type 9 (MMP9) activation and tight-junctions disruption.
“Thus, the complex signaling pathway is constituted by the sequence of selectins, chemokines and integrins at the interface blood/CNS, resulting in emperipolesis through matrix metalloproteinases type 9 (MMP9) activation and tight-junctions disruption [74,75].”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [74]
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Self-citation
- Authors
- Yang, Y., Estrada, E. Y., Thompson, J. F., Liu, W., & Rosenberg, G. A.
- Affiliations
- University of New Mexico Health Sciences Center (US)
- Corresponding author
- Rosenberg, Gary A
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2007-04
- Volume
- 27
- Issue
- 4
- Pages
- 697-709
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- OpenAlex
- W2005675003
- Cited by
- 1,060
- References
- 46
- Citations by year
- 2026: 35 · 2025: 43 · 2024: 37 · 2023: 58 · 2022: 74 · 2021: 67 · 2020: 60 · 2019: 57 · 2018: 55 · 2017: 64 · 2016: 59 · 2015: 65 · 2014: 54 · 2013: 59 · 2012: 56
- FWCI
- 24.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS045847)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- matrix metalloproteinases, tight junction proteins, blood-brain barrier disruption, focal cerebral ischemia, ischemia-reperfusion injury, occludin, claudin-5, MMP-2, MMP-9, MT1-MMP, furin, middle cerebral artery occlusion, astrocytes, cerebral vasculature
- MeSH terms
- Animals, Astrocytes, Blood-Brain Barrier, Cerebral Arteries, Brain Ischemia, Cerebral Veins, Evans Blue, Immunohistochemistry, Male, Membrane Proteins, Nerve Tissue Proteins, Protease Inhibitors, Rats, Inbred SHR, RNA, Messenger, Sucrose, Blotting, Western, Reperfusion Injury, Gelatinases, Tight Junctions, Reverse Transcriptase Polymerase Chain Reaction, Infarction, Middle Cerebral Artery, Enzyme Activators, Matrix Metalloproteinase 2, Matrix Metalloproteinases, Endothelial Cells, Furin, Rats, Matrix Metalloproteinase Inhibitors, Claudin-5, Occludin
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