Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.

Journal of Cellular and Molecular Medicine
Tarah A WordXander H T Wehrens

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca2+ ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca2+ handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca2+ handling and arrhythmic events in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg-176-Glu (R176Q) and a mutation-negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC-CMs were derived using the StemdiffTM kit. Confocal Ca2+ imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca2+ release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentra...Continue Reading

References

Jun 18, 2004·Annals of the New York Academy of Sciences·Stephan E LehnartAndrew R Marks
Jul 29, 2006·Proceedings of the National Academy of Sciences of the United States of America·Prince J KannankerilSusan L Hamilton
Mar 31, 2009·Nature Medicine·Hiroshi WatanabeBjörn C Knollmann
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jérémy FauconnierAlain Lacampagne
Oct 15, 2010·Circulation Journal : Official Journal of the Japanese Circulation Society·Shigeki KobayashiMasunori Matsuzaki
May 28, 2011·Journal of the American College of Cardiology·Christian van der WerfArthur A M Wilde
Jul 30, 2011·Journal of Molecular and Cellular Cardiology·Eleonora Savio Galimberti, Björn C Knollmann
Oct 16, 2013·Journal of Medicinal Chemistry·Chris D SmithThomas G Back
Mar 17, 2015·Proceedings of the National Academy of Sciences of the United States of America·Yan-Ting ZhaoHéctor H Valdivia
Mar 8, 2016·Heart, Lung & Circulation·Jacopo F ImbertiSilvia G Priori
Nov 14, 2016·International Journal of Cardiology·Na LiXander H T Wehrens
Dec 6, 2016·Circulation Journal : Official Journal of the Japanese Circulation Society·Vassilios J BezzeridesWilliam T Pu
Dec 19, 2017·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Robert C KlippJonathan J Abramson
Aug 1, 2018·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Thomas M RostonShubhayan Sanatani
Feb 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Suzanne M BatisteBjorn C Knollmann
May 6, 2020·Annals of Biomedical Engineering·Martti JuholaKatriina Aalto-Setälä

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