Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways
| Autor: | François Mach, Fabrizio Montecucco, Nicolas Vuilleumier, Giovanni G. Camici, Thomas F. Lüscher, Graziano Pelli, Jean-Paul Vallée, Martin F Reiner, Martina Glanzmann, Fabienne Burger, Katia Galan, Alexandre Belin, Alexander Akhmedov, Francesco Paneni, Philipp Jakob, Vincent Braunersreuther |
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| Přispěvatelé: | University of Zurich, Lüscher, Thomas F |
| Rok vydání: | 2014 |
| Předmět: |
Male
STAT3 Transcription Factor Pathology medicine.medical_specialty Src Homology 2 Domain-Containing Transforming Protein 1 MAP Kinase Signaling System Ischemia 610 Medicine & health Apoptosis Myocardial Reperfusion Myocardial Reperfusion Injury Inflammation ddc:616.07 030204 cardiovascular system & hematology Pharmacology ddc:616.0757 2705 Cardiology and Cardiovascular Medicine 03 medical and health sciences 0302 clinical medicine Animals Medicine ddc:576 030304 developmental biology ddc:616 0303 health sciences business.industry Kinase Myocardium Troponin I Signal transducing adaptor protein medicine.disease Mice Inbred C57BL Cytosol Shc Signaling Adaptor Proteins Gene Knockdown Techniques 10209 Clinic for Cardiology medicine.symptom Mitochondrial Swelling Cardiology and Cardiovascular Medicine business Reperfusion injury hormones hormone substitutes and hormone antagonists Biomarkers Gene Deletion Intracellular |
| Zdroj: | European Heart Journal, Vol. 36, No 8 (2015) pp. 516-26 European heart journal |
| ISSN: | 1522-9645 0195-668X |
| DOI: | 10.1093/eurheartj/ehu400 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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