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Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
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Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
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Journal Article
Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
2021
Overview
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.
In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel Na
V
1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
