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Ischemia-reperfusion injury and cardioprotection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency

Siddall, HK; Warrell, CE; Yellon, DM; Mocanu, MM; (2008) Ischemia-reperfusion injury and cardioprotection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency. BASIC RES CARDIOL , 103 (6) 560 - 568. 10.1007/s00395-008-0735-y.

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Abstract

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, P < 0.01). 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.

Type:Article
Title:Ischemia-reperfusion injury and cardioprotection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency
DOI:10.1007/s00395-008-0735-y
Keywords:preconditioning, myocardium, ischemia-reperfusion injury, PTEN, Akt, TUMOR-SUPPRESSOR, DIABETIC HEART, POTENTIAL ROLE, KINASE, AKT, PATHWAY, DEPHOSPHORYLATES, ASSOCIATION, INHIBITION, MYOCARDIUM
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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