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

ABSTRACT: An interplay between Ca2+/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na+ current (INaL) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform NaV1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of NaV1.8, we demonstrate that NaV1.8 contributes to INaL formation. In addition, we reveal a direct interaction between NaV1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of NaV1.8 and CaMKIIδc, we show that NaV1.8-driven INaL is CaMKIIδc-dependent and that NaV1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a NaV1.8 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.

SUBMITTER: Bengel P 

PROVIDER: S-EPMC8593192 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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An interplay between Ca<sup>2+</sup>/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na<sup>+</sup> current (I<sub>NaL</sub>) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na<sub>V</sub>1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na<sub>V</sub>1.8, we demonstrate that Na<sub>V</sub>1.8 contributes to I<sub>NaL</sub> formation. In addition, we rev  ...[more]

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