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 Communications, 12(1) art. 6586. DOI: https://doi.org/10.1038/s41467-021-26690-1
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Details
- 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