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

Author

Listed:
  • Philipp Bengel

    (Georg-August University Göttingen
    partner site Göttingen)

  • Nataliya Dybkova

    (Georg-August University Göttingen
    partner site Göttingen)

  • Petros Tirilomis

    (Georg-August University Göttingen
    partner site Göttingen)

  • Shakil Ahmad

    (Georg-August University Göttingen
    partner site Göttingen
    University Medical Centre Regensburg)

  • Nico Hartmann

    (Georg-August University Göttingen
    partner site Göttingen)

  • Belal Mohamed

    (Georg-August University Göttingen
    partner site Göttingen)

  • Miriam Celine Krekeler

    (Georg-August University Göttingen
    partner site Göttingen)

  • Wiebke Maurer

    (Georg-August University Göttingen
    partner site 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
    partner site Göttingen)

  • Lars S. Maier

    (University Medical Centre Regensburg)

  • Gerd Hasenfuss

    (Georg-August University Göttingen
    partner site Göttingen)

  • Katrin Streckfuss-Bömeke

    (Georg-August University Göttingen
    partner site Göttingen
    University of Würzburg)

  • Samuel Sossalla

    (Georg-August University Göttingen
    partner site Göttingen
    University Medical Centre Regensburg)

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.

Suggested Citation

  • Philipp Bengel & Nataliya Dybkova & Petros Tirilomis & Shakil Ahmad & Nico Hartmann & Belal Mohamed & Miriam Celine Krekeler & Wiebke Maurer & Steffen Pabel & Maximilian Trum & Julian Mustroph & Jan G, 2021. "Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26690-1
    DOI: 10.1038/s41467-021-26690-1
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