Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure

2021 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure​
Bengel, P. ; Dybkova, N.; Tirilomis, P.; Ahmad, S. ; Hartmann, N. H. ; A. Mohamed, B. & Krekeler, M. C. et al.​ (2021) 
Nature Communications12(1) art. 6586​.​ DOI: https://doi.org/10.1038/s41467-021-26690-1 

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Authors
Bengel, Philipp ; Dybkova, Nataliya; Tirilomis, Petros; Ahmad, Shakil ; Hartmann, Nico Horst ; A. Mohamed, Belal; Krekeler, Miriam Celine; Maurer, Wiebke; Pabel, Steffen ; Trum, Maximilian; Sossalla, Samuel Tobias 
Abstract
Abstract An interplay between Ca 2+ /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na + current (I NaL ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na V 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na V 1.8, we demonstrate that Na V 1.8 contributes to I NaL formation. In addition, we reveal a direct interaction between Na V 1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na V 1.8 and CaMKIIδc, we show that Na V 1.8-driven I NaL is CaMKIIδc-dependent and that Na V 1.8-inhibtion reduces diastolic SR-Ca 2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na V 1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy.
Issue Date
2021
Journal
Nature Communications 
Project
SFB 1002: Modulatorische Einheiten 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 Toischer (Kardiales Remodeling) 
eISSN
2041-1723
Language
English

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