Ca2+/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca2+ leak in human ischaemic and dilated cardiomyopathy

2014 | journal article; research paper. A publication with affiliation to the University of Göttingen.

Jump to: Cite & Linked | Documents & Media | Details | Version history

Cite this publication

​Ca2+/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca2+ leak in human ischaemic and dilated cardiomyopathy​
Fischer, T. H. ; Eiringhaus, J. ; Dybkova, N.; Foerster, A.; Herting, J. ; Kleinwaechter, A. & Ljubojevic, S. et al.​ (2014) 
European Journal of Heart Failure16(12) pp. 1292​-1300​.​ DOI: https://doi.org/10.1002/ejhf.163 

License

Published Version

Attribution-NonCommercial 3.0 CC BY-NC 3.0

Details

Authors
Fischer, Thomas H. ; Eiringhaus, Jörg ; Dybkova, Nataliya; Foerster, Anna; Herting, Jonas ; Kleinwaechter, Astrid; Ljubojevic, Senka; Schmitto, Jan D.; Streckfuss-Boemeke, Katrin ; Renner, André; Gummert, Jan; Hasenfuß, Gerd ; Maier, Lars S. ; Sossalla, Samuel 
Abstract
AimsThe sarcoplasmic reticulum (SR) Ca2+ leak is an important pathomechanism in heart failure (HF). It has been suggested that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is only relevant for the induction of the SR Ca2+ 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). Methods and resultsWestern blots showed a significantly increased expression (by 549%) 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 Ca2+ sparks (confocal microscopy) as well as of major arrhythmic events (Ca2+ waves, spontaneous Ca2+ transients). Despite a slightly smaller size of Ca2+ sparks in DCM (P<0.01), the calculated SR Ca2+ leak [Ca2+ spark frequecy (CaSpF)xamplitudexwidthxduration] did not differ between CMs of ICM vs. DCM. Importantly, CaMKII inhibition by autocamide-2-related inhibitory peptide (AIP, 1 mu mol/L) reduced the SR Ca2+ leak by approximate to 80% in both aetiologies (P<0.05 each) and effectively decreased the ratio of arrhythmic cells (P<0.05). Conclusion<p id="ejhf163-para-0003">Functional and molecular measures of the SR Ca2+ 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.
Issue Date
2014
Journal
European Journal of Heart Failure 
Project
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz 
SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur 
Working Group
RG Hasenfuß (Transition zur Herzinsuffizienz) 
RG L. Maier (Experimentelle Kardiologie) 
RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung) 
RG T. Fischer 
ISSN
1388-9842
eISSN
1879-0844

Reference

Citations


Social Media