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Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy

Shende, Pankaj ; Xu, Lifen ; Morandi, Christian ; Pentassuglia, Laura ; Heim, Philippe ; Lebboukh, Sonia ; Berthonneche, Corinne ; Pedrazzini, Thierry ; Kaufmann, Beat A. ; Hall, Michael N. ; Rüegg, Markus A. ; Brink, Marijke

In: Cardiovascular Research, 2016, vol. 109, no. 1, p. 103-114

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    Titre
    • Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy
    Auteur
    • Shende, Pankaj. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    • Xu, Lifen. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    • Morandi, Christian. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    • Pentassuglia, Laura. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    • Heim, Philippe. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    • Lebboukh, Sonia. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    • Berthonneche, Corinne. Department of Medicine and Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland
    • Pedrazzini, Thierry. Department of Medicine and Cardiovascular Assessment Facility, University of Lausanne Medical School, Lausanne, Switzerland
    • Kaufmann, Beat A.. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    • Hall, Michael N.. Biozentrum, University of Basel, Basel, Switzerland
    • Rüegg, Markus A.. Biozentrum, University of Basel, Basel, Switzerland
    • Brink, Marijke. Department of Biomedicine, University of Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Cardiovascular Research, 2016, vol. 109, no. 1, p. 103-114. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:331430
    Summary
    Abstract Aims Mammalian target of rapamycin (mTOR), a central regulator of growth and metabolism, has tissue-specific functions depending on whether it is part of mTOR complex 1 (mTORC1) or mTORC2. We have previously shown that mTORC1 is required for adaptive cardiac hypertrophy and maintenance of function under basal and pressure-overload conditions. In the present study, we aimed to identify functions of mTORC2 in the heart. Methods and results Using tamoxifen-inducible cardiomyocyte-specific gene deletion, we generated mice deficient for cardiac rapamycin-insensitive companion of mTOR (rictor), an essential and specific component of mTORC2. Under basal conditions, rictor deficiency did not affect cardiac growth and function in young mice and also had no effects in adult mice. However, transverse aortic constriction caused dysfunction in the rictor-deficient hearts, whereas function was maintained in controls after 1 week of pressure overload. Adaptive increases in cardiac weight and cardiomyocyte cross-sectional area, fibrosis, and hypertrophic and metabolic gene expression were not different between the rictor-deficient and control mice. In control mice, maintained function was associated with increased protein levels of rictor, protein kinase C (PKC)βII, and PKCδ, whereas rictor ablation abolished these increases. Rictor deletion also significantly decreased PKCε at baseline and after pressure overload. Our data suggest that reduced PKCε and the inability to increase PKCβII and PKCδ abundance are, in accordance with their known function, responsible for decreased contractile performance of the rictor-deficient hearts. Conclusion Our study demonstrates that mTORC2 is implicated in maintaining contractile function of the pressure-overloaded male mouse heart.