SGK1 inhibition shortens action potential duration in LQT3 mice and LQT2 rabbits via inhibition of late sodium current
Abstract Body (Do not enter title and authors here): Background: Serum and glucocorticoid regulated kinase 1 (SGK1) activation during pathological conditions has been shown to increase late sodium current, prolong action potential duration (APD), and induce ventricular arrhythmias, thus recapitulating a long QT syndrome (LQTS) phenotype. Hence, pharmacological SGK1 inhibition may be a novel therapeutic approach in inherited LQTS. Aim: We aimed to investigate potential effects of SGK1 inhibition in animal models of different LQTS subtypes, and the potential involvement of late INa inhibition. Methods: Cardiomyocytes (CMs) isolated from wild-type (WT) and LQT3 mice (Scn5a-1798insD) as well as from WT, LQT1 (KCNQ1-Y315S) and LQT2 (KCNH2-G628S) rabbits, were incubated for 3-5 hours with SGK1-inhibitor (SGK1-inh, 300 nM-3 μM) or DMSO (vehicle). Patch-clamp experiments were performed to assess AP properties, short-term variability (STV) of APD and late INa. Result: SGK1-inh incubation significantly shortened the prolonged APD90 in LQT3 CMs by 23% and in LQT2 CMs by 25% (restoring them towards the WT level), without affecting other AP properties. In contrast, in WT and LQT1 CMs, no effect of SGK1-inh on APD90 was observed. Furthermore, short-term-variability (STV) of APD, a measure of pro-arrhythmia, was pathologically increased in LQT3 (5.6±0.2 ms vs WT 2.7±0.3 ms, p<0.05) and LQT2 (14.7±2.8 ms vs WT 5.9 ±1.1 ms, p < 0.0001), but not in LQT1. SGK1-Inh markedly reduced STV in LQT3 (to 2.9±0.1 ms) and LQT2 CMs (to 7.2± 1.2 ms), but had no effect in WT and LQT1 CMs. While enhanced late INa was previously demonstrated in LQT3 CMs, we now also observed increased late INa in LQT2 CMs as compared to WT (-0.14 ± 0.02 pA/pF vs WT -0.08 ± 0.02 pA/pF, p < 0.005), but not in LQT1 CMs. SGK1-Inh significantly reduced late INa in LQT3 (by 32%) and LQT2 CMs (by 43%), but not in LQT1 CMs, confirming that SGK1-inh directly targets late INa. Conclusion: SGK1-inhibition exerts a beneficial APD-shortening and anti-arrhythmic effect in LQT3 and LQT2 by reducing the enhanced late INa associated with these LQTS genetic subtypes. These findings furthermore underscore the contribution of increased late INa to the LQT2 phenotype.
Barbieri, Miriam
( University of Bern
, Bern
, Switzerland
)
Casini, Simona
( Academic Medical Center
, Amsterdam
, Netherlands
)
Louradour, Julien
( University of Bern
, Bern
, Switzerland
)
De Waal, Tanja M.
( Academic Medical Center
, Amsterdam
, Netherlands
)
Sager, Philip
( Thryv Therapeutics Inc
, Montreal
, Quebec
, Canada
)
Wilde, Arthur
( Academic Medical Center
, Amsterdam
, Netherlands
)
Odening, Katja
( University of Bern
, Bern
, Switzerland
)
Remme, Carol Ann
( Academic Medical Center
, Amsterdam
, Netherlands
)
Author Disclosures:
Miriam Barbieri:DO NOT have relevant financial relationships
| Simona Casini:No Answer
| Julien Louradour:DO NOT have relevant financial relationships
| Tanja M. de Waal:No Answer
| Philip Sager:DO have relevant financial relationships
;
Employee:Thryv Therapeutics:Active (exists now)
| Saumya Das:DO have relevant financial relationships
;
Consultant:Thryv Therapeutics:Active (exists now)
; Research Funding (PI or named investigator):Bristol Myers Squibb:Active (exists now)
; Research Funding (PI or named investigator):Abbott Labs:Past (completed)
; Ownership Interest:Switch Therapeutics:Active (exists now)
; Ownership Interest:Thryv Therapeutics:Active (exists now)
| Arthur Wilde:No Answer
| Katja Odening:DO NOT have relevant financial relationships
| Carol Ann Remme:No Answer
