title: Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts.
abstract: OBJECTIVE
  Because ouabain activates several pathways that are critical to cardioprotective mechanisms such as ischemic preconditioning, we tested if this digitalis compound could protect the heart against ischemia-reperfusion injury through activation of the Na+,K+-ATPase/c-Src receptor complex.
  
  
  RESULTS
  In Langendorff-perfused rat hearts, a short (4 min) administration of ouabain 10 muM followed by an 8-minute washout before 30 min of global ischemia and reperfusion improved cardiac function, decreased lactate dehydrogenase release and reduced infarct size by 40%. Western blot analysis revealed that ouabain activated the cardioprotective phospholipase Cgamma1/protein kinase Cepsilon (PLC-gamma1/PKCepsilon) pathway. Pre-treatment of the hearts with the Src kinase family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2) blocked not only ouabain-induced activation of PLC-gamma1/PKCepsilon pathway, but also cardiac protection. This protection was also blocked by a PKCepsilon translocation inhibitor peptide (PKCepsilon TIP).
  
  
  CONCLUSIONS
  Short exposure to a low concentration of ouabain protects the heart against ischemia/reperfusion injury. This effect of ouabain on the heart is most likely due to the activation of the Na+,K+-ATPase/c-Src receptor complex and subsequent stimulation of key mediators of preconditioning, namely PLC-gamma1 and PKCepsilon.
authors.affiliation: Department of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, Medical University of Ohio, 3035 Arlington Avenue, Toledo, OH 43614-5804, USA.
authors.forename: Sandrine V
authors.initials: SV
authors.lastname: Pierre
authors.forename: Changjun
authors.initials: C
authors.lastname: Yang
authors.forename: Zhaokan
authors.initials: Z
authors.lastname: Yuan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Seminerio
authors.forename: Christian
authors.initials: C
authors.lastname: Mouas
authors.forename: Keith D
authors.initials: KD
authors.lastname: Garlid
authors.forename: Pierre
authors.initials: P
authors.lastname: Dos-Santos
authors.forename: Zijian
authors.initials: Z
authors.lastname: Xie
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010042:Ouabain / Q000627:therapeutic use*; D010477:Perfusion; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C412373:AG 1879; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D010042:Ouabain; D007770:L-Lactate Dehydrogenase; D019061:src-Family Kinases; D051744:Protein Kinase C-epsilon; D000254:Sodium-Potassium-Exchanging ATPase