Inhibition of elevated Ca2+/calmodulin-dependent protein kinase II improves contractility in human failing myocardium.
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.
Sossalla
Samuel
S
Department of Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
Fluschnik
Nina
N
Schotola
Hanna
H
Ort
Katharina R
KR
Neef
Stefan
S
Schulte
Timo
T
Wittköpper
Katrin
K
Renner
André
A
Schmitto
Jan D
JD
Gummert
Jan
J
El-Armouche
Ali
A
Hasenfuss
Gerd
G
Maier
Lars S
LS
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
D047428:Protein Kinase Inhibitors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2