Alexander Akhmedov1, Fabrizio Montecucco2, Vincent Braunersreuther3, Giovanni G Camici1, Philipp Jakob1, Martin F Reiner1, Martina Glanzmann1, Fabienne Burger2, Francesco Paneni4, Katia Galan3, Graziano Pelli3, Nicolas Vuilleumier5, Alexandre Belin6, Jean-Paul Vallée6, Francois Mach3, Thomas F Lüscher7. 1. Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland Department of Cardiology, University Heart Center, Center for Molecular Cardiology, University Hospital and University of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland. 2. Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 3. Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland. 4. Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland Department of Cardiology, University Heart Center, Center for Molecular Cardiology, University Hospital and University of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. 5. Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Switzerland Department of Human Protein Science, Geneva Faculty of Medicine, Geneva, Switzerland. 6. Department of Radiology, CIBM, Geneva University Hospital, Geneva, Switzerland. 7. Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland Department of Cardiology, University Heart Center, Center for Molecular Cardiology, University Hospital and University of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland cardiotfl@gmx.ch.
Abstract
AIMS: Several intracellular mediators have been implicated as new therapeutic targets against myocardial ischaemia and reperfusion injury. However, clinically effective salvage pathways remain undiscovered. Here, we focused on the potential role of the adaptor protein p66(Shc) as a regulator of myocardial injury in a mouse model of cardiac ischaemia and reperfusion. METHODS AND RESULTS: Adult male p66(Shc) deficient (p66(Shc) (-/-)) and C57Bl/6 wild-type (WT) mice were exposed to 30, 45, or 60 min of ischaemia and reperfusion (5, 15 min, or 24 h). Infarct size, systemic and intracardiac inflammation and oxidants, as well as cytosolic and mitochondrial apoptotic pathways were investigated. Following 30, but not 45 or 60 min of ischaemia, genetic p66(Shc) deficiency was associated with larger infarcts. In WT mice, in vivo p66(Shc) knock down by siRNA with transient protein deficiency confirmed these findings. P66(Shc) inhibition was not associated with any modification in post-infarction inflammation, oxidative burst nor cardiac vessel density or structure. However, in p66(Shc) (-/-) mice activation of the protective and anti-apoptotic Reperfusion Injury Salvage Kinases and Survivor Activating Factor Enhancement pathways were blunted and mitochondrial swelling and cellular apoptosis via the caspase-3 pathway increased compared with WT. CONCLUSIONS: Genetic deletion of p66(Shc) increased susceptibility to myocardial injury in response to short-term ischaemia and reperfusion in mice. Still, additional studies are needed for assessing the role of this pathway in acute coronary syndrome patients. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Several intracellular mediators have been implicated as new therapeutic targets against myocardial ischaemia and reperfusion injury. However, clinically effective salvage pathways remain undiscovered. Here, we focused on the potential role of the adaptor protein p66(Shc) as a regulator of myocardial injury in a mouse model of cardiac ischaemia and reperfusion. METHODS AND RESULTS: Adult male p66(Shc) deficient (p66(Shc) (-/-)) and C57Bl/6 wild-type (WT) mice were exposed to 30, 45, or 60 min of ischaemia and reperfusion (5, 15 min, or 24 h). Infarct size, systemic and intracardiac inflammation and oxidants, as well as cytosolic and mitochondrial apoptotic pathways were investigated. Following 30, but not 45 or 60 min of ischaemia, genetic p66(Shc) deficiency was associated with larger infarcts. In WT mice, in vivo p66(Shc) knock down by siRNA with transient protein deficiency confirmed these findings. P66(Shc) inhibition was not associated with any modification in post-infarction inflammation, oxidative burst nor cardiac vessel density or structure. However, in p66(Shc) (-/-) mice activation of the protective and anti-apoptotic Reperfusion Injury Salvage Kinases and Survivor Activating Factor Enhancement pathways were blunted and mitochondrial swelling and cellular apoptosis via the caspase-3 pathway increased compared with WT. CONCLUSIONS: Genetic deletion of p66(Shc) increased susceptibility to myocardial injury in response to short-term ischaemia and reperfusion in mice. Still, additional studies are needed for assessing the role of this pathway in acute coronary syndromepatients. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Robert A Kloner; David A Brown; Marie Csete; Wangde Dai; James M Downey; Roberta A Gottlieb; Sharon L Hale; Jianru Shi Journal: Nat Rev Cardiol Date: 2017-07-27 Impact factor: 32.419