Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
| Autor: | Stefan Wagner, Wiebke Maurer, Hendrik Milting, Nico Hartmann, Katrin Streckfuss-Bömeke, Julian Mustroph, Belal A. Mohamed, Maximilian Trum, P Tirilomis, Lars S. Maier, Karl Toischer, Miriam Celine Krekeler, Jan Gummert, Senka Ljubojevic-Holzer, Steffen Pabel, Gerd Hasenfuss, Samuel Sossalla, Nataliya Dybkova, Shakil Ahmad, Philipp Bengel |
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| Rok vydání: | 2021 |
| Předmět: |
Gene isoform
Science Diastole Cardiology 610 Medizin General Physics and Astronomy Mice Transgenic Pharmacology environment and public health General Biochemistry Genetics and Molecular Biology Article NAV1.8 Voltage-Gated Sodium Channel Mice In vivo medicine Animals Homeostasis Humans Myocytes Cardiac Protein kinase A Proarrhythmia Heart Failure Mice Knockout ddc:610 Multidisciplinary Molecular medicine Chemistry Sodium channel musculoskeletal neural and ocular physiology Arrhythmias Cardiac General Chemistry medicine.disease nervous system Heart failure NAV1 cardiovascular system CRISPR-Cas Systems Calcium-Calmodulin-Dependent Protein Kinase Type 2 tissues |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021) Nature Communications |
| DOI: | 10.5283/epub.52058 |
| Popis: | 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. In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel NaV1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model. |
| Databáze: | OpenAIRE |
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