Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

Gang Li; Brittany D Brumback; Lei Huang; David M Zhang; Tiankai Yin; Catherine E Lipovsky; Stephanie C Hicks; Jesus Jimenez; Patrick M Boyle; Stacey L Rentschler

doi:10.1016/j.jacbts.2022.04.007

Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

JACC Basic Transl Sci. 2022 Aug 31;7(10):1001-1017. doi: 10.1016/j.jacbts.2022.04.007. eCollection 2022 Oct.

Authors

Gang Li^{1

2}, Brittany D Brumback^{1

2}, Lei Huang¹, David M Zhang¹, Tiankai Yin¹, Catherine E Lipovsky^{1

3}, Stephanie C Hicks¹, Jesus Jimenez¹, Patrick M Boyle⁴, Stacey L Rentschler^{1

2

3}

Affiliations

¹ Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA.
² Department of Biomedical Engineering, Washington University McKelvey School of Engineering in St. Louis, Missouri, USA.
³ Department of Developmental Biology, Washington University School of Medicine in St. Louis, Missouri, USA.
⁴ Department of Bioengineering, Center for Cardiovascular Biology, and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.

Abstract

Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered.

Keywords: ABC, active β-catenin; APD, action potential duration; BDM, 2,3-butanedione monoxime; CV, conduction velocity; Cx43, connexin 43; GNa, sodium-channel conductance; GOF, gain of function; GSK-3 inhibitor; GSK-3, glycogen synthase kinase 3; INa, sodium current; LV, left ventricle; NaV1.5, pore-forming α-subunit protein of the voltage-gated cardiac sodium channel; PCR, polymerase chain reaction; RMP, resting membrane potential; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; SB2, SB216763; SB216763; cDNA, complementary DNA; dVm/dtmax, maximum upstroke velocity; electrophysiology; human cardiac slices.

Abstract

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