title: Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.affiliation: 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.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.affiliation: 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.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.affiliation: 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.
authors.forename: Philipp
authors.initials: P
authors.lastname: Jakob
authors.affiliation: 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.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Reiner
authors.affiliation: 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.
authors.forename: Martina
authors.initials: M
authors.lastname: Glanzmann
authors.affiliation: 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.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paneni
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland.
authors.forename: Katia
authors.initials: K
authors.lastname: Galan
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland.
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
authors.affiliation: Department of Radiology, CIBM, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belin
authors.affiliation: Department of Radiology, CIBM, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vallée
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Mach
authors.affiliation: 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.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D008933:Mitochondrial Swelling / Q000235:genetics; D015425:Myocardial Reperfusion / Q000379:methods; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019210:Troponin I / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050796:STAT3 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C494087:Stat3 protein, mouse; D019210:Troponin I
keywords: Acute myocardial infarction; Inflammation; Ischaemia; Reperfusion