PHLPP1 Gene Deletion Protects the Brain from Ischemic Injury
| Autor: | Patrick D. Lyden, Joan Heller Brown, Jessica A. Van Winkle, Nicole H. Purcell, Bo Chen |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Brain Infarction
medicine.medical_specialty Programmed cell death Phosphatase Ischemia Nerve Tissue Proteins Biology Carbohydrate metabolism Mice In vivo Internal medicine Phosphoprotein Phosphatases medicine Animals Phosphorylation Protein kinase B Mice Knockout Neurons PHLPP Nuclear Proteins medicine.disease Molecular biology Enzyme Activation Oxygen Pleckstrin homology domain Glucose Endocrinology Neurology Astrocytes Brain Injuries Reperfusion Injury Original Article Neurology (clinical) Cardiology and Cardiovascular Medicine Proto-Oncogene Proteins c-akt Gene Deletion Signal Transduction |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism. 33:196-204 |
| ISSN: | 1559-7016 0271-678X |
| DOI: | 10.1038/jcbfm.2012.150 |
| Popis: | A recently discovered protein phosphatase PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) has been shown to dephosphorylate Akt on its hydrophobic motif (Ser473) thereby decreasing Akt kinase activity. We generated PHLPP1 knockout (KO) mice and used them to explore the ability of enhanced in vivo Akt signaling to protect the brain against ischemic insult. Brains from KO mice subjected to middle cerebral artery occlusion (MCAO) for 2 hours showed significantly greater increases in Akt activity and less neurovascular damage after reperfusion than wild-type (WT) mice. Remarkably, infarct volume in the PHLPP1 KO was significantly reduced compared with WT (12.7 ± 2.7% versus 22.9 ± 3.1%) and this was prevented by Akt inhibition. Astrocytes from KO mice and neurons in which PHLPP1 was downregulated showed enhanced Akt activation and diminished cell death in response to oxygen-glucose deprivation. Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO. Inhibition of PHLPP could be a therapeutic approach to minimize damage after focal ischemia. |
| Databáze: | OpenAIRE |
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