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

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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.

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Acknowledgments

We thank Professor Ramon Parsons and Professor Dario Alessi for their generous gift of the PTEN+/− mouse model. For breeding advice we would like to thank Gail Fraser from Dundee University and Richard Pugh from UCL. We thank British Heart Foundation for providing the funding for this research.

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Authors and Affiliations

  1. The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX, UK

    Hilary K. Siddall, Clare E. Warrell,  Derek M. Yellon & Mihaela M. Mocanu

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  1. Hilary K. Siddall
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  2. Clare E. Warrell
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  3. Derek M. Yellon
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  4. Mihaela M. Mocanu
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Corresponding author

Correspondence to Derek M. Yellon.

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Returned for 1. Revision: 29 November 2007 1. Revision received: 5 May 2008

Returned for 2. Revision: 2 June 2008 2. Revision received: 5 June 2008

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Siddall, H.K., Warrell, C.E., Yellon, D.M. et al. Ischemia-reperfusion injury and cardioprotection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency. Basic Res Cardiol 103, 560–568 (2008). https://doi.org/10.1007/s00395-008-0735-y

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  • DOI: https://doi.org/10.1007/s00395-008-0735-y

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