title: Inhibition of elevated Ca2+/calmodulin-dependent protein kinase II improves contractility in human failing myocardium.
abstract: BACKGROUND
  Heart failure (HF) is known to be associated with increased Ca(2+)/calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium.
  
  
  OBJECTIVE
  We sought to investigate detailed CaMKIIδ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility.
  
  
  RESULTS
  Expression analysis revealed that CaMKIIδ, both cytosolic δ(C) and nuclear δ(B) splice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca(2+) loading. This was confirmed in isolated myocytes by a reduced SR Ca(2+) spark frequency and hence SR Ca(2+) leak, resulting in increased SR Ca(2+) load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca(2+) leak, was found to be markedly reduced in KN-93-treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae.
  
  
  CONCLUSIONS
  The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKIIδ expression is increased. The mechanism proposed consists of a reduced SR Ca(2+) leak and consequently increased SR Ca(2+) load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.
authors.affiliation: Department of Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.forename: Nina
authors.initials: N
authors.lastname: Fluschnik
authors.forename: Hanna
authors.initials: H
authors.lastname: Schotola
authors.forename: Katharina R
authors.initials: KR
authors.lastname: Ort
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Timo
authors.initials: T
authors.lastname: Schulte
authors.forename: Katrin
authors.initials: K
authors.lastname: Wittköpper
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.forename: Jan D
authors.initials: JD
authors.lastname: Schmitto
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D002478:Cells, Cultured; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012756:Sheep
chemical_list: D047428:Protein Kinase Inhibitors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2