Ischemia-reperfusion injury and cardioprotection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency
| Autor: | Clare Warrell, Hilary K. Siddall, Mihaela M. Mocanu, Derek M. Yellon |
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| Rok vydání: | 2007 |
| Předmět: |
Male
medicine.medical_specialty Genotype Physiology Phosphatase Myocardial Infarction Mice Phosphatidylinositol 3-Kinases Physiology (medical) Internal medicine medicine PTEN Animals cardiovascular diseases Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Cardioprotection PHLPP biology business.industry Myocardium PTEN Phosphohydrolase Protein phosphatase 2 Disease Models Animal Endocrinology Haplotypes Reperfusion Injury Ischemic Preconditioning Myocardial biology.protein Ischemic preconditioning Cardiology and Cardiovascular Medicine business Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Basic research in cardiology. 103(6) |
| ISSN: | 1435-1803 |
| Popis: | Activation of the PI3K/Akt pathway protects the heart from ischemia-reperfusion injury (IRI). The phosphatase PTEN is the main negative regulator of this pathway. We hypothesized that reduced PTEN levels could protect against IRI. Isolated perfused mouse hearts from PTEN(+/-) and their littermates PTEN(+/+) (WT), were subjected to 35 min global ischemia and 30 min reperfusion, with and without 2, 4 or 6 cycles ischemic preconditioning (IPC). The end point was infarct size, expressed as a percentage of the myocardium at risk (I/R%). PTEN and Akt levels were determined using Western blot analysis. Unexpectedly, there were no significant differences in infarction between PTEN(+/-) and WT (42.1 +/- 5.0% Vs. 45.6 +/- 3.3%). However, the preconditioning threshold was significantly reduced in the PTEN(+/-) Vs. WT, with 4 cycles of IPC being sufficient to reduce I/R%, compared to 6 cycles in the WT (4 cycles IPC: 29.8. +/- 3.69% in PTEN(+/-) Vs. 45.5. +/- 5.08% in WT, P0.01). In addition, the ratio between the phospho/total Akt (Ser473 and Thr308) was slightly but significantly increased in the PTEN(+/-) indicating an upregulation of PI3K/Akt pathway. Interestingly, the levels of the other phosphatases that may negatively regulate the PI3K/Akt pathway (PP2A, SHIP2 and PHLPP) were not significantly different between littermates and PTEN(+/-). In conclusion, PTEN haploinsufficiency alone does not induce cardioprotection in this model; however, it reduces the threshold of protection induced by IPC. |
| Databáze: | OpenAIRE |
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