Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
Philipp Bengel, Nataliya Dybkova, Petros Tirilomis, Shakil Ahmad, Nico Hartmann, Belal A. Mohamed, Miriam Celine Krekeler, Wiebke Maurer, Steffen Pabel, Maximilian Trum, Julian Mustroph, Jan Gummert, Hendrik Milting, Stefan Wagner, Senka Ljubojević-Holzer, Karl Toischer, Lars S. Maier, Gerd Hasenfuß, Katrin Streckfuß‐Bömeke, Samuel Sossalla
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.