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 |
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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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