1. Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
- Author
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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, and Philipp Bengel
- Subjects
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 - 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., 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.
- Published
- 2021
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