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The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression

Miranda, Melroy X. ; van Tits, Lambertus J. ; Lohmann, Christine ; Arsiwala, Tasneem ; Winnik, Stephan ; Tailleux, Anne ; Stein, Sokrates ; Gomes, Ana P. ; Suri, Vipin ; Ellis, James L. ; Lutz, Thomas A. ; Hottiger, Michael O. ; Sinclair, David A. ; Auwerx, Johan ; Schoonjans, Kristina ; Staels, Bart ; Lüscher, Thomas F. ; Matter, Christian M.

In: European Heart Journal, 2015, vol. 36, no. 1, p. 51-59

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    Titre
    • The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression
    Auteur
    • Miranda, Melroy X.. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    • van Tits, Lambertus J.. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    • Lohmann, Christine. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    • Arsiwala, Tasneem. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    • Winnik, Stephan. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    • Tailleux, Anne. Institut Pasteur de Lille, Université Lille 2, INSERM UMR1011, EGID, Lille, France
    • Stein, Sokrates. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    • Gomes, Ana P.. Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Genetics Department, Harvard Medical School, Boston, MA, USA
    • Suri, Vipin. Sirtris, a GSK Company, Cambridge, MA, USA
    • Ellis, James L.. Sirtris, a GSK Company, Cambridge, MA, USA
    • Lutz, Thomas A.. Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
    • Hottiger, Michael O.. Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
    • Sinclair, David A.. Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Genetics Department, Harvard Medical School, Boston, MA, USA
    • Auwerx, Johan. Laboratory of Integrative & Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL) Switzerland, Lausanne, Switzerland
    • Schoonjans, Kristina. Laboratory of Integrative & Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL) Switzerland, Lausanne, Switzerland
    • Staels, Bart. Institut Pasteur de Lille, Université Lille 2, INSERM UMR1011, EGID, Lille, France
    • Lüscher, Thomas F.. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    • Matter, Christian M.. Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • European Heart Journal, 2015, vol. 36, no. 1, p. 51-59. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:294017
    Summary
    Aims The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture. Methods and results Apolipoprotein E-deficient (Apoe−/−) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg−1 diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr−/− mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis. Conclusion We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis