title: Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion.
abstract: BACKGROUND
  Timely restoration of coronary blood flow is the only way to salvage myocardium from infarction, but reperfusion per se brings on additional injury. Such reperfusion injury and the resulting size of myocardial infarction is attenuated by ischemic postconditioning, ie, the repeated brief interruption of coronary blood flow during early reperfusion. The signal transduction of ischemic postconditioning is under intense investigation, but no signaling step has yet been identified as causal for such protection in larger mammals in situ.
  
  
  OBJECTIVE
  We have now in an in situ pig model of regional myocardial ischemia/reperfusion addressed the role of mitochondrial signal transducer and activator of transcription 3 (STAT3).
  
  
  RESULTS
  We demonstrated reduction of infarct size by ischemic postconditioning (26 ± 3% of area at risk versus 38 ± 2% in controls with immediate full reperfusion) along with more markedly increased tyrosine(705) phosphorylation of STAT3 in myocardial biopsies (at 10 minutes reperfusion: 9.2 ± 3.0-fold from baseline versus 6.6 ± 2.9-fold in controls with immediate full reperfusion). Increased tyrosine(705) phosphorylation of STAT3 and better preservation of complex 1 respiration and calcium retention capacity were also present in isolated mitochondria from postconditioned myocardium in vitro. Prior janus kinase/STAT inhibition with AG490 in vivo abrogated the infarct size reduction and the better preservation of mitochondrial function, and the STAT3 inhibitor Stattic in vitro also abrogated better preservation of mitochondrial function.
  
  
  CONCLUSIONS
  Our data support a causal role for mitochondrial STAT3 activation to mediate cardioprotection through better mitochondrial function.
authors: Institut für Pathophysiologie, Universitätsklinikum Essen, Germany. gerd.heusch@uk-essen.de
authors: Gerd
authors: G
authors: Heusch
authors: Judith
authors: J
authors: Musiolik
authors: Nilguen
authors: N
authors: Gedik
authors: Andreas
authors: A
authors: Skyschally
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D057775:Ischemic Postconditioning; D053612:Janus Kinases / Q000378:metabolism; D008929:Mitochondria, Heart / Q000502:physiology*; D023421:Models, Animal; D010101:Oxygen Consumption; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050791:STAT Transcription Factors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D034421:Sus scrofa; D013552:Swine; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D003499:Cyclic S-Oxides; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C517409:stattic; D003576:Electron Transport Complex IV; D053612:Janus Kinases; D002118:Calcium