| First Author | Bengel P | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 6586 |
| PubMed ID | 34782600 | Mgi Jnum | J:322051 |
| Mgi Id | MGI:6826734 | Doi | 10.1038/s41467-021-26690-1 |
| Citation | Bengel P, et al. (2021) Detrimental proarrhythmogenic interaction of Ca(2+)/calmodulin-dependent protein kinase II and NaV1.8 in heart failure. Nat Commun 12(1):6586 |
| abstractText | An interplay between Ca(2+)/calmodulin-dependent protein kinase IIdeltac (CaMKIIdeltac) 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 CaMKIIdeltac-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 CaMKIIdeltac in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of NaV1.8 and CaMKIIdeltac, we show that NaV1.8-driven INaL is CaMKIIdeltac-dependent and that NaV1.8-inhibtion reduces diastolic SR-Ca(2+) leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIdeltac-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 CaMKIIdeltac downstream target which may constitute a prognostic and antiarrhythmic strategy. |
