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  • Title: Interactions between p38 mitogen-activated protein kinase and caspase-3 in cerebral endothelial cell death after hypoxia-reoxygenation.
    Author: Lee SR, Lo EH.
    Journal: Stroke; 2003 Nov; 34(11):2704-9. PubMed ID: 14551401.
    Abstract:
    BACKGROUND AND PURPOSE: The emerging concept of the neurovascular unit in stroke reemphasizes the need to focus on endothelial responses in brain. In this study we examined the role of mitogen-activated protein (MAP) kinase signaling in the regulation of hypoxic cell death in cerebral endothelial cells. METHODS: Human cerebral microvascular endothelial cells were exposed to 4 to 12 hours of hypoxia followed by 12 to 24 hours of reoxygenation. Cytotoxicity was measured by quantifying lactate dehydrogenase release. DNA laddering and caspase-3 activity were assessed to document a role for caspase-dependent cell death. zVAD-fmk and zDEVD-fmk were used to inhibit caspases. Activation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) was assessed with Western blotting and kinase activity assays. U0126, SB203580, and SP600125 were used to interrupt the ERK, p38, and JNK pathways, respectively. RESULTS: Endothelial cell death occurred primarily during reoxygenation. DNA laddering and caspase activation were observed, and cytotoxicity was ameliorated by caspase inhibitors (20 micromol/L of zVAD-fmk or zDEVD-fmk). Among the 3 major MAP kinases, only p38 was transiently activated during reoxygenation, and inhibition with 10 micromol/L of SB203580 significantly reduced cytotoxicity. No effects were observed with other MAP kinase inhibitors. Cytoprotection with SB203580 was not accompanied by caspase downregulation. In contrast, cytoprotection with zVAD-fmk was associated with a decrease in p38 activation. Furthermore, cleavage of MEKK1 (an upstream kinase of p38) was significantly reduced by zVAD-fmk. CONCLUSIONS: Cerebral endothelial cell death after hypoxia-reoxygenation is mediated by interactions between caspases and p38 MAP kinase. Surprisingly, p38 pathways lie downstream of caspase mechanisms in this model system.
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