title: Inhibition of protein kinase C alpha improves myocardial beta-adrenergic receptor signaling and ventricular function in a model of myocardial preservation.
abstract: OBJECTIVE
  The specific effect of protein kinase C alpha, the primary ventricular calcium-dependent protein kinase C isoform, on myocardial protection is unclear. The objective of this study was to determine the role of protein kinase C alpha in myocardial protection and recovery of function after cardioplegic arrest, cold preservation, and normothermic reperfusion, as relevant to cardiac transplantation.
  
  
  METHODS
  We used an ex vivo murine model, and hearts were arrested with cold crystalloid cardioplegia or saline as a control and maintained at 4 degrees C for 4 hours. This was followed by normothermic reperfusion for 90 minutes. Transgenic hearts with cardiac-specific activation or inhibition of protein kinase C alpha were then studied to specifically examine the effects of protein kinase C alpha on myocardial preservation in this model.
  
  
  RESULTS
  Cardioplegic arrest with University of Wisconsin solution led to significantly improved postreperfusion hemodynamics and inhibition of myocardial protein kinase C alpha activity relative to that seen in saline-treated control hearts. Beta-adrenergic receptor signaling was also preserved with University of Wisconsin solution. Transgenic hearts with enhanced protein kinase C alpha activity had poor postreperfusion hemodynamics, impaired beta-adrenergic receptor signaling, and increased G protein-coupled receptor kinase 2 activity compared with those seen in nontransgenic control hearts. In contrast, transgenic hearts with inhibited protein kinase C alpha activity had even better myocardial protection relative to control hearts and preserved beta-adrenergic receptor signaling.
  
  
  CONCLUSIONS
  Current techniques of myocardial preservation are associated with inhibition of protein kinase C alpha activity and maintenance of intact beta-adrenergic receptor signaling. Activation of protein kinase C alpha leads to enhanced beta-adrenergic receptor desensitization and impaired signaling and ventricular function as a result of increased G protein-coupled receptor kinase 2 activity. This is a novel in vivo mechanism of G protein-coupled receptor kinase 2 activation. Strategies to specifically inhibit these kinases might improve long-term myocardial protection.
authors.affiliation: Department of Surgery, Section of Cardiothoracic Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: D'Souza
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Petrashevskaya
authors.forename: Walter H
authors.initials: WH
authors.lastname: Merrill
authors.forename: Shahab A
authors.initials: SA
authors.lastname: Akhter
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002314:Cardioplegic Solutions / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005978:Glutathione / Q000494:pharmacology; D006324:Heart Arrest, Induced; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions / Q000494:pharmacology*; D010477:Perfusion; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011887:Raffinose / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D020127:Recovery of Function; D015398:Signal Transduction
chemical_list: D002314:Cardioplegic Solutions; D002316:Cardiotonic Agents; D007328:Insulin; D019188:Organ Preservation Solutions; D011943:Receptors, Adrenergic, beta; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D051571:Protein Kinase C-alpha; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose