Hartmann, Nico and Knierim, Maria and Maurer, Wiebke and Dybkova, Nataliya and Zeman, Florian and Hasenfuss, Gerd and Sossalla, Samuel and Streckfuss-Boemeke, Katrin (2024) NaV1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 25 (11): 6144. ISSN 1661-6596, 1422-0067
Full text not available from this repository. (Request a copy)Abstract
The sodium channel Na(V)1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that Na(V)1.8 contributes to arrhythmogenesis by inducing a persistent Na+ current (late Na+ current, I-NaL) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of Na(V)1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that I-NaL was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of Na(V)1.8. In contrast, we did not find any effects on ventricular APD(90). The frequency of spontaneous sarcoplasmic reticulum Ca2+ sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of Na(V)1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of Na(V)1.8 in control cells. In conclusion, we show that Na(V)1.8-induced I-NaL primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca2+ release. The inhibition or knockout of Na(V)1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms Na(V)1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LATE SODIUM CURRENT; LATE I-NA; CHRONIC HEART-FAILURE; ATRIAL-FIBRILLATION; DELAYED AFTERDEPOLARIZATIONS; DOG CARDIOMYOCYTES; CURRENT INHIBITION; HYDROGEN-PEROXIDE; CHANNEL; RANOLAZINE; Na(V)1.8; SCN10A; ventricular arrhythmias; induced pluripotent stem cells; CRISPR Cas9; ventricular cells |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Zentrum für Klinische Studien |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jan 2026 08:32 |
| Last Modified: | 28 Jan 2026 08:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65218 |
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