title: Ca(2+) /calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca(2+) leak in human ischaemic and dilated cardiomyopathy.
abstract: OBJECTIVE
  The sarcoplasmic reticulum (SR) Ca(2+) leak is an important pathomechanism in heart failure (HF). It has been suggested that Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is only relevant for the induction of the SR Ca(2+) leak in non-ischaemic but not in ischaemic HF. Therefore, we investigated CaMKII and its targets as well as the functional effects of CaMKII inhibition in human ischaemic cardiomyopathy (ICM, n = 37) and dilated cardiomyopathy (DCM, n = 40).
  
  
  RESULTS
  Western blots showed a significantly increased expression (by 54 ± 9%) and autophosphorylation at Thr286 (by 129 ± 29%, P < 0.05 each) of CaMKII in HF compared with healthy myocardium. However, no significant difference could be detected in ICM compared with DCM as to the expression and autophosphorylation of CaMKII nor the phosphorylation of the target sites ryanodine receptor 2 (RyR2)-S2809, RyR2-S2815, and phospholamban-Thr17. Isolated human cardiomyocytes (CMs) of patients with DCM and ICM showed a similar frequency of diastolic Ca(2+) sparks (confocal microscopy) as well as of major arrhythmic events (Ca(2+) waves, spontaneous Ca(2+) transients). Despite a slightly smaller size of Ca(2+) sparks in DCM (P < 0.01), the calculated SR Ca(2+) leak [Ca(2+) spark frequecy (CaSpF) × amplitude × width × duration] did not differ between CMs of ICM vs. DCM. Importantly, CaMKII inhibition by autocamide-2-related inhibitory peptide (AIP, 1 µmol/L) reduced the SR Ca(2+) leak by ∼80% in both aetiologies (P < 0.05 each) and effectively decreased the ratio of arrhythmic cells (P < 0.05).
  
  
  CONCLUSIONS
  Functional and molecular measures of the SR Ca(2+) leak are comparable in human ICM and DCM. CaMKII is equally responsible for the induction of the 'RyR2 leakiness' in both pathologies. Thus, CaMKII inhibition as a therapeutic measure may not be restricted to patients suffering from DCM but rather may be beneficial for the majority of HF patients.
authors.affiliation: Abteilung Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.forename: Jörg
authors.initials: J
authors.lastname: Eiringhaus
authors.forename: Nataliya
authors.initials: N
authors.lastname: Dybkova
authors.forename: Anna
authors.initials: A
authors.lastname: Förster
authors.forename: Jonas
authors.initials: J
authors.lastname: Herting
authors.forename: Astrid
authors.initials: A
authors.lastname: Kleinwächter
authors.forename: Senka
authors.initials: S
authors.lastname: Ljubojevic
authors.forename: Jan D
authors.initials: JD
authors.lastname: Schmitto
authors.forename: Katrin
authors.initials: K
authors.lastname: Streckfuß-Bömeke
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
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: D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000201:enzymology*; D005260:Female; D006333:Heart Failure / Q000473:pathology; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000201:enzymology; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D010455:Peptides; D019837:Ryanodine Receptor Calcium Release Channel; C514527:autocamptide-2-related inhibitory peptide II; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Arrhythmias; CaMKII; Heart failure; SR Ca2+ leak