Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 24, Issue 7, Pages 720-727Publisher
SAGE PUBLICATIONS INC
DOI: 10.1097/01.WCB.0000122747.72175.47
Keywords
matrix metalloproteinases; caspase; cerebral ischemia; blood-brain barrier
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Funding
- NINDS NIH HHS [R01-NS40529, R01-NS38731, R01-NS37074, P50-NS10828] Funding Source: Medline
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Matrix metalloproteinases (MMPs) may contribute to the pathophysiology of cerebral ischemia by degrading matrix components in the neurovascular unit. In this study, the authors document a pathway by which MMPs interfere with cell-matrix interactions and trigger caspase-mediated cytotoxicity in brain endothelial cells. Hypoxia-reoxygenation induced endothelial cytotoxicity. Cytoprotection with zDEVD-fmk confirmed that cell death was partly caspase mediated. The temporal profile of caspase-3 activation was matched by elevations in MMP-2 and MMP-9. MMP inhibitors significantly decreased caspase-3 activation and reduced endothelial cell death. Degradation of matrix fibronectin confirmed the presence of extracellular proteolysis. Increasing integrin-linked kinase signaling with the beta1 integrin-activating antibody (8A2) ameliorated endothelial cytotoxicity. The results suggest that MMP-9 and MMP-2 contribute to caspase-mediated brain endothelial cell death after hypoxia-reoxygenation by disrupting cell-matrix interactions and homeostatic integrin signaling.
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