title: Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure.
abstract: BACKGROUND
  The conventional protein kinase C (PKC) isoform alpha functions as a proximal regulator of Ca2+ handling in cardiac myocytes. Deletion of PKCalpha in the mouse results in augmented sarcoplasmic reticulum Ca2+ loading, enhanced Ca2+ transients, and augmented contractility, whereas overexpression of PKCalpha in the heart blunts contractility. Mechanistically, PKCalpha directly regulates Ca2+ handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca2+ ATPase.
  
  
  RESULTS
  In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCalpha-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCalpha cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCalpha was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology.
  
  
  CONCLUSIONS
  Pharmacological inhibition of PKCalpha, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hambleton
authors.forename: Harvey
authors.initials: H
authors.lastname: Hahn
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kuhn
authors.forename: Raisa
authors.initials: R
authors.lastname: Klevitsky
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Carr
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Kimball
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Hewett
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D002118:Calcium / Q000032:analysis / Q000502:physiology; D002303:Cardiac Output, Low / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D004247:DNA / Q000032:analysis / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D015316:Genetic Therapy; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D007211:Indoles; D011758:Pyrroles; C085989:Ro 32-0432; D004247:DNA; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D002118:Calcium; C064758:Ro 31-8220