Investigating LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Autor: Polina Baskin, Eloisa Arbustini, Ofer Binah, Mihaela Gherghiceanu, Binyamin Eisen, Michael Arad, Yuval Shemer, Lucy N. Mekies, Rita Shulman, Brenda Gerull, Danielle Regev, Eyal Gottlieb, Ronen Ben Jehuda
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Heart disease
Action Potentials
Stimulation
030204 cardiovascular system & hematology
LMNA
Pacemaker potential
0302 clinical medicine
Myocytes
Cardiac
Biology (General)
Induced pluripotent stem cell
Spectroscopy
health care economics and organizations
integumentary system
Dilated cardiomyopathy
Cell Differentiation
General Medicine
Middle Aged
Lamin Type A
Computer Science Applications
Pedigree
Chemistry
embryonic structures
Cardiology
Female
Adult
Cardiomyopathy
Dilated
medicine.medical_specialty
congenital
hereditary
and neonatal diseases and abnormalities
QH301-705.5
Induced Pluripotent Stem Cells
arrhythmia
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Internal medicine
medicine
Humans
ddc:610
Physical and Theoretical Chemistry
Molecular Biology
QD1-999
business.industry
Organic Chemistry
Arrhythmias
Cardiac
medicine.disease
electrophysiology
Electrophysiological Phenomena
dilated cardiomyopathy
Electrophysiology
030104 developmental biology
Mutation
Calcium
iPSC-CMs
business
Lamin
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 7874, p 7874 (2021)
Volume 22
Issue 15
ISSN: 1422-0067
Popis: LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients’ induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (If) density
(2) prolonged action potential duration and increased L-type Ca2+ current (ICa,L) density
(3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability
(4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na+/Ca2+ exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.
Databáze: OpenAIRE
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