title: Inhibition of PKCα/β with ruboxistaurin antagonizes heart failure in pigs after myocardial infarction injury.
abstract: BACKGROUND
  Protein kinase Cα (PKCα) activity and protein level are induced during cardiac disease where it controls myocardial contractility and propensity to heart failure in mice and rats. For example, mice lacking the gene for PKCα have enhanced cardiac contractility and reduced susceptibility to heart failure after long-term pressure overload or after myocardial infarction injury. Pharmacological inhibition of PKCα/β with Ro-32-0432, Ro-31-8220 or ruboxistaurin (LY333531) similarly enhances cardiac function and antagonizes heart failure in multiple models of disease in both mice and rats.
  
  
  OBJECTIVE
  Large and small mammals differ in several key indexes of heart function and biochemistry, lending uncertainty as to how PKCα/β inhibition might affect or protect a large animal model of heart failure.
  
  
  RESULTS
  We demonstrate that ruboxistaurin administration to a pig model of myocardial infarction-induced heart failure was protective. Twenty-kilogram pigs underwent left anterior descending artery occlusion resulting in myocardial infarctions and were then divided into vehicle or ruboxistaurin feed groups, after which they were monitored monthly for the next 3 months. Ruboxistaurin administered pigs showed significantly better recovery of myocardial contractility 3 months after infarction injury, greater ejection fraction, and greater cardiac output compared with vehicle-treated pigs.
  
  
  CONCLUSIONS
  These results provide additional evidence in a large animal model of disease that PKCα/β inhibition (with ruboxistaurin) represents a tenable and novel therapeutic approach for treating human heart failure.
authors: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors: Dennis
authors: D
authors: Ladage
authors: Lisa
authors: L
authors: Tilemann
authors: Kiyotake
authors: K
authors: Ishikawa
authors: Robert N
authors: RN
authors: Correll
authors: Yoshiaki
authors: Y
authors: Kawase
authors: Steven R
authors: SR
authors: Houser
authors: Jeffery D
authors: JD
authors: Molkentin
authors: Roger J
authors: RJ
authors: Hajjar
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D054059:Coronary Occlusion / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000209:etiology* / Q000517:prevention & control*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000150:complications* / Q000209:etiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011758:Pyrroles; C085989:Ro 32-0432; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; C064758:Ro 31-8220