TY - JOUR
T1 - Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction
AU - Li, Gang
AU - Brumback, Brittany D.
AU - Huang, Lei
AU - Zhang, David M.
AU - Yin, Tiankai
AU - Lipovsky, Catherine E.
AU - Hicks, Stephanie C.
AU - Jimenez, Jesus
AU - Boyle, Patrick M.
AU - Rentschler, Stacey L.
N1 - Funding Information:
This study has received grants from the National Science Foundation (NSF) and the National Institutes of Health (NIH): NSF GRFP DGE-1745038 and NIH T32 HL125241-03 to Ms Brumback, NIH T32HL007081 to Dr Jimenez, NIH T32HL134635 to Mr Zhang, and NIH R01 HL 130212 and UH3 HL 141800 to Dr Rentschler. Dr Rentschler holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Funding Information:
The authors thank Dr Michael K. Pasque and Mid-America Transplant Services for procurement of heart tissue and the families of the organ donors for their generous gifts that make this research possible. They also thank the National Science Foundation (NSF) and the National Institutes of Health (NIH) for their ongoing support
Publisher Copyright:
© 2022 The Authors
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - GSK-3 inhibitor
KW - SB216763
KW - electrophysiology
KW - human cardiac slices
UR - http://www.scopus.com/inward/record.url?scp=85139733745&partnerID=8YFLogxK
U2 - 10.1016/j.jacbts.2022.04.007
DO - 10.1016/j.jacbts.2022.04.007
M3 - Article
C2 - 36337924
AN - SCOPUS:85139733745
SN - 2452-302X
VL - 7
SP - 1001
EP - 1017
JO - JACC: Basic to Translational Science
JF - JACC: Basic to Translational Science
IS - 10
ER -