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      The role of PI3Kα isoform in cardioprotection

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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.

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          The online version of this article (doi:10.1007/s00395-017-0657-7) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          The mitochondrial permeability transition pore and its role in cell death.

          M Crompton (1999)
          This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke 'accidental' apoptosis.
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            A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.

            Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
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              Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy.

              An unresolved question in cardiac biology is whether distinct signaling pathways are responsible for the development of pathological and physiological cardiac hypertrophy in the adult. Physiological hypertrophy is characterized by a normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is associated with an altered pattern of cardiac gene expression, fibrosis, cardiac dysfunction, and increased morbidity and mortality. The elucidation of signaling cascades that play distinct roles in these two forms of hypertrophy will be critical for the development of more effective strategies to treat heart failure. We examined the role of the p110alpha isoform of phosphoinositide 3-kinase (PI3K) for the induction of pathological hypertrophy (pressure overload-induced) and physiological hypertrophy (exercise-induced) by using transgenic mice expressing a dominant negative (dn) PI3K(p110alpha) mutant specifically in the heart. dnPI3K transgenic mice displayed significant hypertrophy in response to pressure overload but not exercise training. dnPI3K transgenic mice also showed significant dilation and cardiac dysfunction in response to pressure overload. Thus, PI3K(p110alpha) appears to play a critical role for the induction of physiological cardiac growth but not pathological growth. PI3K(p110alpha) also appears essential for maintaining contractile function in response to pathological stimuli.
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                Author and article information

                Contributors
                0044 020 3447 9888 , d.yellon@ucl.ac.uk
                Journal
                Basic Res Cardiol
                Basic Res. Cardiol
                Basic Research in Cardiology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0300-8428
                1435-1803
                17 October 2017
                17 October 2017
                2017
                : 112
                : 6
                : 66
                Affiliations
                [1 ]ISNI 0000000121901201, GRID grid.83440.3b, The Hatter Cardiovascular Institute, , University College London, ; 67 Chenies Mews, London, WC1E 6HX UK
                [2 ]ISNI 0000 0004 0385 4466, GRID grid.443909.3, Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Quimicas y Farmaceuticas and Facultad de Medicina, , Universidad de Chile, ; Santiago, Chile
                [3 ]ISNI 0000000121901201, GRID grid.83440.3b, UCL Cancer Institute, , University College London, ; London, UK
                Article
                657
                10.1007/s00395-017-0657-7
                5645445
                29043508
                e4f50e5e-9568-43a5-85ff-763fd8b8e095
                © The Author(s) 2017

                Open AccessThis 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.

                History
                : 6 September 2017
                : 12 October 2017
                Funding
                Funded by: Fundacion Rafael del Pino
                Funded by: FONDECYT 3160298.
                Funded by: FundRef http://dx.doi.org/10.13039/501100000274, British Heart Foundation;
                Categories
                Original Contribution
                Custom metadata
                © Springer-Verlag GmbH Germany 2017

                Cardiovascular Medicine
                cardioprotection,phosphoinositide 3-kinase,ischemic preconditioning,ischemia/reperfusion injury

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