Document Detail


Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways.
MedLine Citation:
PMID:  25336219     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Alexander Akhmedov; Fabrizio Montecucco; Vincent Braunersreuther; Giovanni G Camici; Philipp Jakob; Martin F Reiner; Martina Glanzmann; Fabienne Burger; Francesco Paneni; Katia Galan; Graziano Pelli; Nicolas Vuilleumier; Alexandre Belin; Jean-Paul Vallée; Francois Mach; Thomas F Lüscher
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-21
Journal Detail:
Title:  European heart journal     Volume:  -     ISSN:  1522-9645     ISO Abbreviation:  Eur. Heart J.     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-22     Completed Date:  -     Revised Date:  2014-10-23    
Medline Journal Info:
Nlm Unique ID:  8006263     Medline TA:  Eur Heart J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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