Molecular and functional relevance of Na\(_V\)1.8-induced atrial arrhythmogenic triggers in a human SCN10A knock-out stem cell model
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- In heart failure and atrial fibrillation, a persistent Na\(^+\) current (I\(_{NaL}\)) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na\(_V\)1.8 contributes to arrhythmogenesis by inducing a I\(_{NaL}\). Genome-wide association studies indicate that mutations in the SCN10A gene (Na\(_V\)1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na\(_V\)1.8-related effects, whether through cardiac ganglia orIn heart failure and atrial fibrillation, a persistent Na\(^+\) current (I\(_{NaL}\)) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na\(_V\)1.8 contributes to arrhythmogenesis by inducing a I\(_{NaL}\). Genome-wide association studies indicate that mutations in the SCN10A gene (Na\(_V\)1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na\(_V\)1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I\(_{NaL}\) and action potential duration. Ca\(^{2+}\) measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca\(^{2+}\) leak. The I\(_{NaL}\) was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na\(_V\)1.8. No effects on atrial APD\(_{90}\) were detected in any groups. Both SCN10A KO and specific blockers of Na\(_V\)1.8 led to decreased Ca\(^{2+}\) spark frequency and a significant reduction of arrhythmogenic Ca\(^{2+}\) waves. Our experiments demonstrate that Na\(_V\)1.8 contributes to I\(_{NaL}\) formation in human atrial CMs and that Na\(_V\)1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na\(_V\)1.8 could be a new target for antiarrhythmic strategies.…
Autor(en): | Nico HartmannORCiD, Maria Knierim, Wiebke Maurer, Nataliya Dybkova, Gerd Hasenfuß, Samuel SossallaORCiD, Katrin Streckfuss-BömekeORCiD |
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URN: | urn:nbn:de:bvb:20-opus-362708 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Institut für Pharmakologie und Toxikologie |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | International Journal of Molecular Sciences |
ISSN: | 1422-0067 |
Erscheinungsjahr: | 2023 |
Band / Jahrgang: | 24 |
Heft / Ausgabe: | 12 |
Aufsatznummer: | 10189 |
Originalveröffentlichung / Quelle: | International Journal of Molecular Sciences (2023) 24:12, 10189. https://doi.org/10.3390/ijms241210189 |
DOI: | https://doi.org/10.3390/ijms241210189 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | CRISPR Cas9; Na\(_V\)1.8; iPSC-cardiomyocytes; late Na\(^+\) current (I\(_{NaL}\)) |
Datum der Freischaltung: | 11.06.2024 |
Lizenz (Deutsch): | ![]() |