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The role of PI3Kα isoform in cardioprotection

Rossello, X; Riquelme, JA; He, Z; Taferner, S; Vanhaesebroeck, B; Davidson, SM; Yellon, DM; (2017) The role of PI3Kα isoform in cardioprotection. Basic Research in Cardiology , 112 , Article 66. 10.1007/s00395-017-0657-7. Green open access

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Abstract

Ischemic preconditioning (IPC) limits myocardial infarct size through the activation of the PI3K–Akt signal cascade; however, little is known about the roles of individual PI3K isoforms in cardioprotection. We aimed, therefore, to elucidate the role of the PI3Kα isoform in cardioprotection Pharmacological PI3Kα inhibition was assessed in isolated-perfused mouse hearts subjected to ischemia/reperfusion injury (IRI), either during the IPC procedure or at reperfusion. PI3Kα inhibition abrogated the IPC-induced protective effect at reperfusion, but not when given only during the IPC protocol. These results were confirmed in an in vivo model. Moreover, pharmacological PI3Kα activation by insulin at reperfusion was sufficient to confer cardioprotection against IRI. In addition, PI3Kα was shown to be expressed and activated in mouse cardiomyocytes, mouse cardiac endothelial cells, as well as in mouse and human heart tissue. Furthermore, PI3Kα was shown to mediate its effect though the inhibition of mitochondrial permeability transition pore opening. In conclusion, PI3Kα activity is required during the early reperfusion phase to reduce myocardial infarct size. This suggests that strategies specifically enhancing the α isoform of PI3K at reperfusion promote tissue salvage and as such, and could provide a direct target for clinical treatment of IRI.

Type: Article
Title: The role of PI3Kα isoform in cardioprotection
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00395-017-0657-7
Publisher version: http://doi.org/10.1007/s00395-017-0657-7
Language: English
Additional information: © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, Cardioprotection, Phosphoinositide 3-kinase, Ischemic preconditioning, Ischemia/reperfusion injury, PERMEABILITY TRANSITION PORE, RANDOMIZED CONTROLLED-TRIAL, GLUCOSE-INSULIN-POTASSIUM, INJURY SALVAGE KINASE, MOUSE HEART MODEL, REPERFUSION INJURY, MYOCARDIAL-INFARCTION, SIGNAL-TRANSDUCTION, ISCHEMIC PRE, P110-ALPHA
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: https://discovery.ucl.ac.uk/id/eprint/10028215
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