Bengel, Philipp and Dybkova, Nataliya and Tirilomis, Petros and Ahmad, Shakil and Hartmann, Nico and Mohamed, Belal A. and Krekeler, Miriam Celine and Maurer, Wiebke and Pabel, Steffen and Trum, Maximilian and Mustroph, Julian and Gummert, Jan and Milting, Hendrik and Wagner, Stefan and Ljubojevic-Holzer, Senka and Toischer, Karl and Maier, Lars S. and Hasenfuss, Gerd and Streckfuss-Bomeke, Katrin and Sossalla, Samuel (2021) Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and Na(V)1.8 in heart failure. NATURE COMMUNICATIONS, 12 (1): 6586. ISSN , 2041-1723
Full text not available from this repository. (Request a copy)Abstract
In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel Na(V)1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model. An interplay between Ca2+/calmodulin-dependent protein kinase II delta c (CaMKII delta c) 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 CaMKII delta c-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 CaMKII delta c in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na(V)1.8 and CaMKII delta c, we show that Na(V)1.8-driven I-NaL is CaMKII delta c-dependent and that Na(V)1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKII delta c-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 CaMKII delta c downstream target which may constitute a prognostic and antiarrhythmic strategy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LATE SODIUM CURRENT; RETICULUM CA2+ LEAK; DILATED CARDIOMYOPATHY; ATRIAL MYOCARDIUM; CHANNEL NA(V)1.8; NA+ CHANNEL; CAMKII; PHOSPHORYLATION; OVEREXPRESSION; CONTRACTILITY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Sep 2022 05:38 |
| Last Modified: | 12 Sep 2022 05:38 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47051 |
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