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. 2023 Feb 16;4(4):268-274.
doi: 10.1016/j.hroo.2023.02.003. eCollection 2023 Apr.

SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome

Maengjo Kim  1   2   3 , Saumya Das  4   5 , David J Tester  1   2   3 , Sabindra Pradhananga  4 , Samantha K Hamrick  1   2   3 , Xiaozhi Gao  1   2   3 , Dinesh Srinivasan  4 , Philip T Sager  4   6 , Michael J Ackerman  1   2   3
Affiliations

SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome

Maengjo Kim et al. Heart Rhythm O2. .

Abstract

Background: Long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) is proposed as a novel therapeutic for LQTS.

Objective: The study sought to test the efficacy of novel, selective SGK1 inhibitors in induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQTS.

Methods: The mexiletine (MEX)-sensitive SCN5A-P1332L iPSC-CMs were tested initially compared with a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 SCN5A-P1332L variant-corrected isogenic control (IC). The SGK1-I1 therapeutic efficacy, compared with MEX, was tested for APD at 90% repolarization (APD90) shortening in SCN5A-P1332L, SCN5A-R1623Q, KCNH2-G604S, and KCNQ1-V254M iPSC-CMs using FluoVolt.

Results: The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared with its IC (646 ± 7 ms vs 482 ± 23 ms; P < .0001). MEX shortened the APD90 to 560 ± 7 ms (52% attenuation, P < .0001). SGK1-I1 shortened the APD90 to 518 ± 5 ms (78% attenuation, P < .0001) but did not shorten the APD90 in the IC. SGK1-I1 shortened the APD90 of the SCN5A-R1623Q iPSC-CMs (753 ± 8 ms to 475 ± 19 ms compared with 558 ± 19 ms with MEX), the KCNH2-G604S iPSC-CMs (666 ± 10 ms to 574 ± 18 ms vs 538 ± 15 ms after MEX), and the KCNQ1-V254M iPSC-CMs (544 ± 10 ms to 475 ± 11ms; P = .0004).

Conclusions: Therapeutically inhibiting SGK1 effectively shortens the APD in human iPSC-CM models of the 3 major LQTS genotypes. These preclinical data support development of SGK1 inhibitors as novel, first-in-class therapy for patients with congenital LQTS.

Keywords: Long QT syndrome; SGK1; Serum and glucocorticoid regulated kinase-1; Therapeutic; Treatment; iPSC.

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Figures

Figure 1
Figure 1
The action potential duration and serum and glucocorticoid regulated kinase-1 activity are increased in SCN5A-P1332L induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) compared with isogenic control (IC) iPSC-CMs. A: Representative tracings (left) of action potential from SCN5A-P1332L (P1332L) (black line) and IC (gray line) iPSC-CMs. The raw tracings were recorded using a fluorescent voltage dye, FluoVolt. Quantification (right) of action potential duration at 90% repolarization (APD90) of SCN5A-P1332L and IC iPSC-CMs. B: Representative immunoblots of protein lysates of SCN5A-P1332L and IC iPSC-CMs probed for phospho (Ser9)-glycogen synthase kinase beta (p-GSK3β), total GSK3β (T-GSK3β), and GAPDH as a loading control (left). Quantification of band intensity on the immunoblot (right). Protein levels were normalized to GAPDH, and data were expressed as fold change relative to IC.
Figure 2
Figure 2
Action potential duration–shortening effects of a novel serum and glucocorticoid regulated kinase-1 (SGK1) inhibitor compound in long QT syndrome type 3 induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). A: Representative tracings (left) of action potential from SCN5A-P1332L iPSC-CMs after 4-hour treatment with mexiletine (MEX) and a novel SGK1 inhibitor, SGK1-I1. The black, gray, and red lines indicated tracing of action potential of dimethyl sulfoxide (DMSO), 10 μM MEX, and 30 nM SGK1-I1, paced at a frequency of 1 Hz, respectively. Quantification (right) of action potential duration at 90% repolarization (APD90) of SCN5A-P1332L iPSC-CMs after compound treatment. The dotted line indicates the APD90 of isogenic control iPSC-CMs at baseline. B: Representative tracings (left) of action potential from SCN5A-R1623Q iPSC-CMs after 4-hour treatment with MEX and SGK1-I1. The black, gray, and red lines indicated tracing of the action potential of DMSO, 10 μM MEX, and 3 nM SGK1-I1, paced at a frequency of 1 Hz, respectively. Quantification (right) of APD90 of SCN5A-R1623Q iPSC-CMs after compound treatment.
Figure 3
Figure 3
Action potential duration–shortening effects of a novel serum and glucocorticoid regulated kinase-1 (SGK1) inhibitor compound in long QT syndrome type 1 and type 2 induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). A: Representative tracings (left) of action potential from KCNQ1-V254M iPSC-CMs after 4-hour treatment with mexiletine (MEX) and an SGK1 inhibitor, SGK1-I1. The black, gray, and red lines indicated tracing of action potential of dimethyl sulfoxide (DMSO), 10 μM MEX, and 100 nM SGK1-I1, paced at a frequency of 1 Hz, respectively. Quantification (right) of action potential duration at 90% repolarization (APD90) of KCNQ1-V254M iPSC-CMs after compound treatment. B: Representative tracings (left) of action potential from KCNH2-G604S iPSC-CMs after 4-hour treatment with MEX and SGK1-I1. The black, gray, and red lines indicated tracing of action potential of DMSO, 10 μM MEX, and 30 nM SGK1-I1, paced at a frequency of 1 Hz, respectively. Quantification (right) of APD90 of KCNH2-G604S iPSC-CMs after compound treatment.
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