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 Mohamed, Miriam Celine Krekeler, Wiebke Maurer, Steffen Pabel, Maximilian Trum, Julian Mustroph, Jan Gummert, Hendrik Milting, Stefan Wagner, Senka Ljubojevic-Holzer, Karl Toischer, Lars S. Maier, Gerd Hasenfuss, Katrin Streckfuss-Bömeke and Samuel Sossalla ()
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Philipp Bengel: Georg-August University Göttingen
Nataliya Dybkova: Georg-August University Göttingen
Petros Tirilomis: Georg-August University Göttingen
Shakil Ahmad: Georg-August University Göttingen
Nico Hartmann: Georg-August University Göttingen
Belal Mohamed: Georg-August University Göttingen
Miriam Celine Krekeler: Georg-August University Göttingen
Wiebke Maurer: Georg-August University Göttingen
Steffen Pabel: University Medical Centre Regensburg
Maximilian Trum: University Medical Centre Regensburg
Julian Mustroph: University Medical Centre Regensburg
Jan Gummert: Heart and Diabetes Centre North Rhine-Westphalia
Hendrik Milting: Heart and Diabetes Centre North Rhine-Westphalia
Stefan Wagner: University Medical Centre Regensburg
Senka Ljubojevic-Holzer: Medical University of Graz
Karl Toischer: Georg-August University Göttingen
Lars S. Maier: University Medical Centre Regensburg
Gerd Hasenfuss: Georg-August University Göttingen
Katrin Streckfuss-Bömeke: Georg-August University Göttingen
Samuel Sossalla: Georg-August University Göttingen

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26690-1

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DOI: 10.1038/s41467-021-26690-1

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