Ischemic Preconditioning: Neuronal Survival in the Face of Caspase-3 Activation
| Autor: | I. Cappuccio, Teresa Jover, Agata Calderone, R. Suzanne Zukin, Michael V. L. Bennett, Monica Simionescu, Hidenori Yokota, Hidenobu Tanaka |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Programmed cell death Cell Survival Blotting Western Ischemia Caspase 3 DNA Fragmentation Receptors Nerve Growth Factor Receptor Nerve Growth Factor Neuroprotection Brain Ischemia Inhibitor of Apoptosis Proteins Mitochondrial Proteins Rats Sprague-Dawley In Situ Nick-End Labeling medicine Animals HSP70 Heat-Shock Proteins Ischemic Preconditioning Tissue homeostasis Caspase Neurons Deoxyribonucleases biology General Neuroscience Proteins medicine.disease Caspase 9 Rats Up-Regulation Cell biology Enzyme Activation Disease Models Animal Cytoprotection Apoptosis Caspases biology.protein Ischemic preconditioning Apoptosis Regulatory Proteins Carrier Proteins Cellular/Molecular |
| Zdroj: | The Journal of Neuroscience. 24:2750-2759 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.5475-03.2004 |
| Popis: | Apoptosis is an evolutionarily conserved process critical to tissue development and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes inappropriate cell death. Global ischemia is a neuronal insult that induces delayed cell death with many features of apoptosis. Ischemic preconditioning affords robust protection of CA1 neurons against a subsequent severe ischemic challenge. The molecular mechanisms underlying ischemic tolerance are unclear. Here we show that ischemia induces pronounced caspase-3 activity in naive neurons that die and in preconditioned neurons that survive. Preconditioning intervenes downstream of proteolytic processing and activation of caspase-3 (a protease implicated in the execution of apoptosis) and upstream of the caspase-3 target caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA fragmentation) to arrest neuronal death. We further show that global ischemia promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), a factor that neutralizes the protective actions of IAPs and promotes neuronal death. Preconditioning blocks the mitochondrial release of Smac/DIABLO, but not the ischemia-induced upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death cascade and arrests neuronal death. These findings suggest that preconditioning preserves the integrity of the mitochondrial membrane, enabling neurons to survive in the face of caspase activation. |
| Databáze: | OpenAIRE |
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