title: Ca2+/calmodulin-dependent protein kinase II and protein kinase A differentially regulate sarcoplasmic reticulum Ca2+ leak in human cardiac pathology.
abstract: BACKGROUND
  Sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptor type 2 (RyR2) dysfunction is of major pathophysiological relevance in human heart failure (HF); however, mechanisms underlying progressive RyR2 dysregulation from cardiac hypertrophy to HF are still controversial.
  
  
  RESULTS
  We investigated healthy control myocardium (n=5) and myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In hypertrophy, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both phosphorylated RyR2 at levels that were not different from healthy myocardium. Accordingly, inhibitors of these kinases reduced the SR Ca(2+) leak. In HF, however, the SR Ca(2+) leak was nearly doubled compared with hypertrophy, which led to reduced systolic Ca(2+) transients, a depletion of SR Ca(2+) storage and elevated diastolic Ca(2+) levels. This was accompanied by a significantly increased CaMKII-dependent phosphorylation of RyR2. In contrast, PKA-dependent RyR2 phosphorylation was not increased in HF and was independent of previous β-blocker treatment. In HF, CaMKII inhibition but not inhibition of PKA yielded a reduction of the SR Ca(2+) leak. Moreover, PKA inhibition further reduced SR Ca(2+) load and systolic Ca(2+) transients.
  
  
  CONCLUSIONS
  In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca(2+) leak. In the transition from hypertrophy to HF, the diastolic Ca(2+) leak increases and disturbed Ca(2+) cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction.
authors.affiliation: Abteilung Kardiologie und Pneumologie/Herzzentrum, Georg August Universität Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.forename: Jonas
authors.initials: J
authors.lastname: Herting
authors.forename: Theodor
authors.initials: T
authors.lastname: Tirilomis
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: David
authors.initials: D
authors.lastname: Ellenberger
authors.forename: Anna
authors.initials: A
authors.lastname: Förster
authors.forename: Jan D
authors.initials: JD
authors.lastname: Schmitto
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Schöndube
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
mesh_terms: D000368:Aged; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: calcium–calmodulin-dependent protein kinase type 2; heart failure; hypertrophy; protein kinases; sarcoplasmic reticulum