title: Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling.
abstract: BACKGROUND
  Activated protein C (APC) is a vitamin K-dependent plasma serine protease that down-regulates clotting and inflammatory pathways. It is known that APC exerts a cardioprotective effect by decreasing apoptosis of cardiomyocytes and inhibiting expression of inflammatory mediators after myocardial ischemia.
  
  
  OBJECTIVE
  The objective of this study was to understand the mechanism of the APC-mediated cardioprotection against ischemic injury.
  
  
  METHODS
  Cardioprotective activities of wild-type APC and two derivatives, having either dramatically reduced anticoagulant activity or lacking signaling activity, were monitored in an acute ischemia/reperfusion injury model in which the left anterior descending coronary artery (LAD) was occluded.
  
  
  RESULTS
  APC reduced the myocardial infarct size by a mechanism that was largely independent of its anticoagulant activity. Thus, the non-anticoagulant APC-2Cys mutant, but not the non-signaling APC-E170A mutant, attenuated myocardial infarct size by EPCR and PAR-1-dependent mechanisms. Further studies revealed that APC acts directly on cardiomyocytes to stimulate the AMP-activated protein kinase (AMPK) signaling pathway. The activation of AMPK by APC ameliorated the post-ischemic cardiac dysfunction in isolated perfused mouse hearts. Moreover, both APC and APC-2Cys inhibited production of TNFα and IL-6 in vivo by attenuating the ischemia/reperfusion-induced JNK and NF-κB signaling pathways.
  
  
  CONCLUSIONS
  APC exerts a cardioprotective function in ischemic/reperfusion injury through modulation of AMPK, NF-κB and JNK signaling pathways.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo-SUNY, Buffalo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: A R
authors.initials: AR
authors.lastname: Rezaie
authors.forename: J
authors.initials: J
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006321:Heart; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D002316:Cardiotonic Agents; D016328:NF-kappa B; D011486:Protein C; D055372:AMP-Activated Protein Kinases