Detrimental proarrhythmogenic interaction of Ca 2+ /calmodulin-dependent protein kinase II and Na V 1.8 in heart failure

An interplay between Ca /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na current (I ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-card...

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Bibliographic Details
Published in:Nature communications 2021-11, Vol.12 (1), p.6586
Main Authors: Bengel, Philipp, Dybkova, Nataliya, Tirilomis, Petros, Ahmad, Shakil, Hartmann, Nico, A Mohamed, Belal, Krekeler, Miriam Celine, Maurer, Wiebke, Pabel, Steffen, Trum, Maximilian, Mustroph, Julian, Gummert, Jan, Milting, Hendrik, Wagner, Stefan, Ljubojevic-Holzer, Senka, Toischer, Karl, Maier, Lars S, Hasenfuss, Gerd, Streckfuss-Bömeke, Katrin, Sossalla, Samuel
Format: Article
Language:English
Subjects:
Animals
Arrhythmias, Cardiac - metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
CRISPR-Cas Systems
Heart Failure - metabolism
Heart Failure - pathology
Homeostasis - genetics
Humans
Mice
Mice, Knockout
Mice, Transgenic
Molecular Medicine
Myocytes, Cardiac
NAV1.8 Voltage-Gated Sodium Channel - genetics
NAV1.8 Voltage-Gated Sodium Channel - metabolism
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Summary:An interplay between Ca /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na current (I ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na 1.8, we demonstrate that Na 1.8 contributes to I formation. In addition, we reveal a direct interaction between Na 1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na 1.8 and CaMKIIδc, we show that Na 1.8-driven I is CaMKIIδc-dependent and that Na 1.8-inhibtion reduces diastolic SR-Ca leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na 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.
ISSN:2041-1723