دورية أكاديمية
SNTA1 gene rescues ion channel function and is antiarrhythmic in cardiomyocytes derived from induced pluripotent stem cells from muscular dystrophy patients.
| العنوان: | SNTA1 gene rescues ion channel function and is antiarrhythmic in cardiomyocytes derived from induced pluripotent stem cells from muscular dystrophy patients. |
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| المؤلفون: | Jimenez-Vazquez, Eric N, Arad, Michael, Macías, Álvaro, Vera-Pedrosa, Maria L, Cruz, Francisco Miguel, Gutierrez, Lilian K, Cuttita, Ashley J, Monteiro da Rocha, André, Herron, Todd J, Ponce-Balbuena, Daniela, Guerrero-Serna, Guadalupe, Binah, Ofer, Michele, Daniel E, Jalife, José |
| المساهمون: | NIH Research Project Grant Program, Fundación La Caixa, Fundación La Marató TV3, Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Unión Europea. Comisión Europea. H2020, Ministerio de Ciencia e Innovación (España), Fundación ProCNIC, Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), American Heart Association, Israel Science Foundation, Niedersachsen Foundation, US-Israel Binational Science Foundation (BSF), Bernard Lublin Donation, Duchenne Parent Project Netherlands |
| بيانات النشر: | eLife Sciences Publications |
| سنة النشر: | 2022 |
| المجموعة: | REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII) |
| مصطلحات موضوعية: | Calcium-Binding Proteins, Cardiomyopathies, Induced Pluripotent Stem Cells, Membrane Proteins, Muscle Proteins, Muscular Dystrophy, Duchenne, Potassium Channels, Inwardly Rectifying, Action Potentials, Arrhythmias, Cardiac, Dystrophin, Female, Humans, Male, Myocytes |
| الوصف: | Patients with cardiomyopathy of Duchenne Muscular Dystrophy (DMD) are at risk of developing life-threatening arrhythmias, but the mechanisms are unknown. We aimed to determine the role of ion channels controlling cardiac excitability in the mechanisms of arrhythmias in DMD patients. To test whether dystrophin mutations lead to defective cardiac NaV1.5-Kir2.1 channelosomes and arrhythmias, we generated iPSC-CMs from two hemizygous DMD males, a heterozygous female, and two unrelated control males. We conducted studies including confocal microscopy, protein expression analysis, patch-clamping, non-viral piggy-bac gene expression, optical mapping and contractility assays. Two patients had abnormal ECGs with frequent runs of ventricular tachycardia. iPSC-CMs from all DMD patients showed abnormal action potential profiles, slowed conduction velocities, and reduced sodium (INa) and inward rectifier potassium (IK1) currents. Membrane NaV1.5 and Kir2.1 protein levels were reduced in hemizygous DMD iPSC-CMs but not in heterozygous iPSC-CMs. Remarkably, transfecting just one component of the dystrophin protein complex (α1-syntrophin) in hemizygous iPSC-CMs from one patient restored channelosome function, INa and IK1 densities, and action potential profile in single cells. In addition, α1-syntrophin expression restored impulse conduction and contractility and prevented reentrant arrhythmias in hiPSC-CM monolayers. We provide the first demonstration that iPSC-CMs reprogrammed from skin fibroblasts of DMD patients with cardiomyopathy have a dysfunction of the NaV1.5-Kir2.1 channelosome, with consequent reduction of cardiac excitability and conduction. Altogether, iPSC-CMs from patients with DMD cardiomyopathy have a NaV1.5-Kir2.1 channelosome dysfunction, which can be rescued by the scaffolding protein α1-syntrophin to restore excitability and prevent arrhythmias. Supported by National Institutes of Health R01 HL122352 grant; 'la Caixa' Banking Foundation (HR18-00304); Fundación La Marató TV3: Ayudas a la investigación en ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2050-084X |
| العلاقة: | info:eu-repo/grantAgreement/ES/HR18-00304; info:eu-repo/grantAgreement/ES/LA MARATO-2020; info:eu-repo/grantAgreement/ES/CEX2020-001041-S; info:eu-repo/grantAgreement/ES/MICIN/AEI/10.13039/501100011033; Elife. 2022 Jun 28;11:e76576; http://hdl.handle.net/20.500.12105/15427Test; eLife |
| DOI: | 10.7554/eLife.76576 |
| الإتاحة: | https://doi.org/20.500.12105/15427Test https://doi.org/10.7554/eLife.76576Test https://hdl.handle.net/20.500.12105/15427Test |
| حقوق: | http://creativecommons.org/licenses/by/4.0Test/ ; Atribución 4.0 Internacional ; open access |
| رقم الانضمام: | edsbas.99A26026 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 2050084X |
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| DOI: | 10.7554/eLife.76576 |