Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Bengel, P; Dybkova, N; Tirilomis, P; Ahmad, S; Hartmann, N; Mohamed, BA; Krekeler, MC; Maurer, W; Pabel, S; Trum, M; Mustroph, J; Gummert, J; Milting, H; Wagner, S; Ljubojevic-Holzer, S; Toischer, K; Maier, LS; Hasenfuss, G; Streckfuss-Bomeke, K; Sossalla, S.
Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and Na(V)1.8 in heart failure
NAT COMMUN. 2021; 12(1): 6586
Doi: 10.1038/s41467-021-26690-1
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- Co-Autor*innen der Med Uni Graz
- Holzer Senka
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- 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.