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SGK1-inhibition restores cardiac repolarization in LQT2 rabbits and LQT3 mice by reducing late sodium current
Miriam Barbieri1, Simona Casini2, Julien Louradour1
1Translational Cardiology, Department of Physiology, University of Bern, and Department of Cardiology, University Hospital Bern Bühlplatz 5, 3012 Bern, Switzerland.
Abstract:
Current management does not fully prevent arrhythmias in long QT syndrome (LQTS), underscoring a need for novel therapies. Here, we investigated potential beneficial effects of serum/glucocorticoid-regulated-kinase-1 (SGK1)-inhibition in different LQTS animal models. Ventricular cardiomyocytes (CMs) isolated from wild-type (WT), LQT1 (KCNQ1-Y315S) and LQT2 (KCNH2-GS628S) rabbits, and WT and LQT3 (Scn5a-1798insD+/-) mice were incubated for 2-4 h with SGK1-inhibitor (SGK1-inh, 300 nM or 3 μM) or vehicle to assess its effects on action potential duration (APD) and late sodium current (late INa). Whole heart experiments were performed to investigate SGK1-inh effects on QT duration (rabbits) and ventricular effective refractory periods (ERP, mice). Late INa was enhanced in LQT2 and LQT3 CMs, but not in LQT1. SGK1-inh reduced late INa in LQT2 (by 60%) and LQT3 (by 33%) CMs, but not in LQT1. Consequently, SGK1-inh shortened APD in LQT2 (by 25%) and LQT3 CMs (by 23%) restoring these to WT levels, but did not affect APD in LQT1. The proarrhythmic marker short-term-variability of APD was increased in LQT2 and LQT3, and was reduced by SGK1-inh in LQT2 (by 48%) and LQT3 (by 49%) CMs. Additionally, SGK1-inh decreased triggered APs in LQT3 CMs. Finally, SGK1-inh perfusion in ex vivo hearts shortened QT-interval in LQT2 and decreased ventricular ERP in LQT3, restoring them to WT levels. In conclusion, late INa is increased in LQT2 rabbits and LQT3 mice, but not in LQT1 rabbits. SGK1-inhibition shortens APD/QT and reduces proarrhythmic risk in LQT2 and LQT3 CMs by suppressing enhanced late INa, indicating potential therapeutic benefit.
Insights
Serum/glucocorticoid-regulated-kinase-1 (SGK1) inhibition offers a potential new therapy for Long QT syndrome (LQTS). SGK1 inhibition reduces arrhythmias by suppressing late sodium current in LQT2 and LQT3 models.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Pharmacology
Background:
- Current Long QT syndrome (LQTS) management strategies are insufficient in preventing arrhythmias.
- There is a critical need for novel therapeutic approaches to manage LQTS.
- Serum/glucocorticoid-regulated-kinase-1 (SGK1) has emerged as a potential therapeutic target.
Purpose of the Study:
- To investigate the therapeutic potential of SGK1 inhibition in various LQTS animal models.
- To assess the effects of SGK1 inhibition on action potential duration (APD) and late sodium current (late INa).
- To evaluate the impact of SGK1 inhibition on QT duration and ventricular effective refractory periods (ERP).
Main Methods:
- Ventricular cardiomyocytes (CMs) from wild-type (WT), LQT1, LQT2, and LQT3 animal models were treated with an SGK1 inhibitor (SGK1-inh) or vehicle.
- Electrophysiological parameters including APD and late INa were measured.
- Whole-heart experiments assessed QT duration in rabbits and ERP in mice following SGK1-inh perfusion.
Main Results:
- SGK1 inhibition significantly reduced the enhanced late INa in LQT2 (by 60%) and LQT3 (by 33%) cardiomyocytes, but not in LQT1.
- Consequently, SGK1-inh shortened APD in LQT2 (by 25%) and LQT3 (by 23%) CMs, restoring them to WT levels, and reduced proarrhythmic markers.
- In ex vivo hearts, SGK1-inh shortened the QT interval in LQT2 and decreased ventricular ERP in LQT3, normalizing them towards WT levels.
Conclusions:
- SGK1 inhibition effectively suppresses the enhanced late INa in LQT2 and LQT3 models.
- This suppression leads to shortened APD/QT and reduced proarrhythmic risk, indicating therapeutic benefit.
- SGK1 inhibition represents a promising novel therapeutic strategy for specific forms of Long QT syndrome.
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