The neuronal ischemic tolerance Is conditioned by the Tp53 Arg72Pro polymorphism
[EN]Cerebral preconditioning (PC) confers endogenous brain protection after stroke. Ischemic stroke patients with a prior transient ischemic attack (TIA) may potentially be in a preconditioned state. Although PC has been associated with the activation of pro-survival signals, the mechanism by which...
| Autores: | , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Salamanca (USAL) |
| Repositorio: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/155312 |
| Acceso en línea: | https://doi.org/10.1007/s12975-018-0631-1 http://hdl.handle.net/10366/155312 |
| Access Level: | acceso abierto |
| Palabra clave: | Ischemic Preconditioning Neurons Aged Brain Ischemia Glucose Excitatory Amino Acid Agonists Microtubule-Associated Proteins Arginine Electron Transport Complex IV Humans Cells Middle Aged Cerebral Cortex Membrane Potentials Subcellular Fractions Apoptosis Animals Caspase 3 Tumor Suppressor Protein p53 Proline Cohort Studies Cell Hypoxia Mice N-Methylaspartate proteínas asociadas a microtúbulos prolina apoptosis humanos ratones anciano neuronas mediana edad glucosa hipoxia celular N-metilaspartato agonistas de aminoácidos excitadores proteína supresora de tumor p53 corteza cerebral células animales estudios de cohortes arginina caspasa 3 isquemia cerebral complejo IV de transporte de electrones potenciales de membrana fracciones subcelulares preacondicionamiento isquémico |
| Sumario: | [EN]Cerebral preconditioning (PC) confers endogenous brain protection after stroke. Ischemic stroke patients with a prior transient ischemic attack (TIA) may potentially be in a preconditioned state. Although PC has been associated with the activation of pro-survival signals, the mechanism by which preconditioning confers neuroprotection is not yet fully clarified. Recently, we have described that PC-mediated neuroprotection against ischemic insult is promoted by p53 destabilization, which is mediated by its main regulator MDM2. Moreover, we have previously described that the human Tp53 Arg72Pro single nucleotide polymorphism (SNP) controls susceptibility to ischemia-induced neuronal apoptosis and governs the functional outcome of patients after stroke. Here, we studied the contribution of the human Tp53 Arg72Pro SNP on PC-induced neuroprotection after ischemia. Our results showed that cortical neurons expressing the Pro72-p53 variant exhibited higher PC-mediated neuroprotection as compared with Arg72-p53 neurons. PC prevented ischemia-induced nuclear and cytosolic p53 stabilization in Pro72-p53 neurons. However, PC failed to prevent mitochondrial p53 stabilization, which occurs in Arg72-p53 neurons after ischemia. Furthermore, PC promoted neuroprotection against ischemia by controlling the p53/active caspase-3 pathway in Pro72-p53, but not in Arg72-p53 neurons. Finally, we found that good prognosis associated to TIA within 1 month prior to ischemic stroke was restricted to patients harboring the Pro72 allele. Our findings demonstrate that the Tp53 Arg72Pro SNP controls PC-promoted neuroprotection against a subsequent ischemic insult by modulating mitochondrial p53 stabilization and then modulates TIA-induced ischemic tolerance. |
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