Insulin blocks cytochromecrelease in the reperfused brain through PI3-K signaling and by promoting BaxBcl-XLbinding
| Autor: | Rita Kumar, Gary S. Krause, Thomas H. Sanderson, Jonathon M. Sullivan |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment bcl-X Protein Bcl-xL Biochemistry Article Brain Ischemia Phosphatidylinositol 3-Kinases Cellular and Molecular Neuroscience Bcl-2-associated X protein Internal medicine medicine Animals Insulin Rats Long-Evans Protein kinase B bcl-2-Associated X Protein biology Cytochrome c Cytochromes c Rats Cell biology Endocrinology Apoptosis Reperfusion Injury biology.protein Apoptosome Signal transduction Protein Binding Signal Transduction |
| Zdroj: | Journal of Neurochemistry. 106:1248-1258 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/j.1471-4159.2008.05473.x |
| Popis: | The critical event of the intrinsic pathway of apoptosis following transient global brain ischemia is the release of cytochrome c from the mitochondria. In vitro studies have shown that insulin can signal specifically via phosphatidylinositol-3-OH-kinase (PI3-K) and Akt to prevent cytochrome c release. Therefore, insulin may exert its neuroprotective effects during brain reperfusion by blocking cytochrome c release. We hypothesized that insulin acts through PI3-K, Akt, and Bcl-2 family proteins to inhibit cytochrome c release following transient global brain ischemia. We found that a single bolus of insulin given immediately upon reperfusion inhibited cytochrome c release for at least 24 h, and produced a fivefold improvement in neuronal survival at 14 days. Moreover, insulin's ability to inhibit cytochrome c release was completely dependent on PI3-K signaling and insulin induces phosphorylation of Akt through PI3-K. In untreated animals, there was an increase in mitochondrial Bax at 6 h of reperfusion, and Bax binding to Bcl-X(L) was disrupted at the mitochondria. Insulin prevented both these events in a PI3-K-dependent manner. In summary, insulin regulates cytochrome c release through PI3-K likely by activating Akt, promoting the binding between Bax and Bcl-X(L), and by preventing Bax translocation to the mitochondria. |
| Databáze: | OpenAIRE |
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