Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation.
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.
Lee
Sun-Ryung
SR
Neuroprotection Research Laboratory, Department of Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Lo
Eng H
EH
D001921:Brain / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D002534:Hypoxia, Brain / Q000473:pathology*; D019012:Integrin beta1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology*; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D019012:Integrin beta1; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9