Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

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 condu...

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Bibliographic Details
Published in:JACC. Basic to translational science 2022-10, Vol.7 (10), p.1001-1017
Main Authors: Li, Gang, Brumback, Brittany D, Huang, Lei, Zhang, David M, Yin, Tiankai, Lipovsky, Catherine E, Hicks, Stephanie C, Jimenez, Jesus, Boyle, Patrick M, Rentschler, Stacey L
Format: Article
Language:English
Subjects:
Original Research - Preclinical
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Summary: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.
ISSN:2452-302X
2452-302X
DOI:10.1016/j.jacbts.2022.04.007