Inhibition of NaV1.8 prevents atrial arrhythmogenesis in human and mice

URN zum Zitieren dieses Dokuments:: urn:nbn:de:bvb:355-epub-448037
DOI zum Zitieren dieses Dokuments:: 10.5283/epub.44803

Pabel, Steffen ; Ahmad, Shakil ; Tirilomis, Petros ; Stehle, Thea ; Mustroph, Julian

; Holzamer, Andreas ; Hilker, Michael ; Maier, Lars S. ; Sossalla, Samuel ; ; ; ; ;

Vorschau

Lizenz: Creative Commons Namensnennung 4.0 International
PDF - Veröffentlichte Version
(2MB)

Veröffentlichungsdatum dieses Volltextes: 08 Feb 2021 11:41

Alternative Links zum Volltext:DOI Verlag

Diese Publikation ist Teil des DEAL-Vertrags mit Springer.

Details

Vorschau

Indiziert in

Bibliographische Daten exportieren

Zusammenfassung

Zusammenfassung

Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (Na(V)1.8) in atrial electrophysiology. This study investigated the role and involvement of Na(V)1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking Na(V)1.8. Na(V)1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of Na(V)1.8 and Na(V)1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of Na(V)1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of Na(V)1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that Na(V)1.8 significantly contributes to late Na+ current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of Na(V)1.8 potently reduced late Na+ current, proarrhythmic diastolic Ca2+ release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A(-/-) mice (genetic ablation of Na(V)1.8). Pharmacological Na(V)1.8 inhibition showed no effects in SCN10A(-/-) mice. Importantly, in vivo experiments in SCN10A(-/-) mice showed that genetic ablation of Na(V)1.8 protects against atrial fibrillation induction. This study demonstrates that Na(V)1.8 is expressed in the murine and human atria and contributes to late Na+ current generation and cellular arrhythmogenesis. Blocking Na(V)1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.

Nur für Besitzer und Autoren: Kontrollseite des Eintrags

Downloadstatistik

Altmetric

Alternative Statistik (altmetrics)

Weitere Literatur (mittels CORE)

Details

Vorschau

Indiziert in

Bibliographische Daten exportieren

Zusammenfassung

Zusammenfassung

Downloadstatistik

Downloads

Alternative Statistik (altmetrics)

Weitere Literatur (mittels CORE)

Universitätsbibliothek