title: Activation of protein kinases in chronically hypoxic infant human and rabbit hearts: role in cardioprotection.
abstract: BACKGROUND
  Many infants who undergo heart surgery have a congenital cyanotic defect in which the heart is chronically perfused with hypoxic blood. However, the signaling pathways by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia is unknown.
  
  
  RESULTS
  We determined the activation and translocation of protein kinase C (PKC) isoforms and mitogen activated protein kinases (MAP kinases) in 15 infants with cyanotic (SaO2<85%) or acyanotic (SaO2>95%) heart defects undergoing surgical repair and in 80 rabbits raised from birth in a hypoxic (SaO2<85%) or normoxic (SaO2>95%) environment. Tissues from infant human and rabbit hearts were processed for Western and in vitro kinase analysis. In human infants with cyanotic heart defects, PKCepsilon, p38 MAP kinase, and JUN kinase but not p42/44 MAP kinase were activated and translocated from the cytosolic to the particulate fraction compared with acyanotic heart defects. In rabbit infants there was a parallel response for PKCepsilon, p38 MAP kinase, and JUN kinase similar to humans. In infant rabbit hearts inhibition of PKCepsilon with chelerythrine, p38 MAP kinase, with SB203580 and JUN kinase with curcumin abolished the cardioprotective effects of chronic hypoxia but had no effects on normoxic hearts.
  
  
  CONCLUSIONS
  Infant human and rabbit hearts adapt to chronic hypoxia through activation of PKCepsilon, p38 MAP kinase, and JUN kinase signal transduction pathways. These pathways may be responsible for cardioprotection in the chronically hypoxic infant rabbit heart.
authors.affiliation: Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Rafiee
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Kong
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
authors.forename: James S
authors.initials: JS
authors.lastname: Tweddell
authors.forename: S Bert
authors.initials: SB
authors.lastname: Litwin
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mussatto
authors.forename: Robert D
authors.initials: RD
authors.lastname: Jaquiss
authors.forename: Jidong
authors.initials: J
authors.lastname: Su
authors.forename: John E
authors.initials: JE
authors.lastname: Baker
mesh_terms: D051698:Activating Transcription Factor 2; D021581:Active Transport, Cell Nucleus; D000222:Adaptation, Physiological; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002908:Chronic Disease; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006325:Heart Atria / Q000201:enzymology; D006330:Heart Defects, Congenital / Q000150:complications* / Q000601:surgery; D006352:Heart Ventricles / Q000201:enzymology; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000209:etiology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000209:etiology; D009206:Myocardium / Q000201:enzymology*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D002316:Cardiotonic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases