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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Di Pasquale, E. Lodola, F. Miragoli, M. Denegri, M. Avelino-Cruz, J. E. Buonocore, M. Nakahama, H. Portararo, P. Bloise, R. Napolitano, C. Condorelli, G. Priori, S. G. |
| Description | Country affiliation: Italy Author Affiliation: Di Pasquale E ( Istituto di Ricerca Genetica e Biomedica, National Research Council of Italy, Milan, Italy.) |
| Abstract | Induced pluripotent stem cells (iPSC) offer a unique opportunity for developmental studies, disease modeling and regenerative medicine approaches in humans. The aim of our study was to create an in vitro 'patient-specific cell-based system' that could facilitate the screening of new therapeutic molecules for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited form of fatal arrhythmia. Here, we report the development of a cardiac model of CPVT through the generation of iPSC from a CPVT patient carrying a heterozygous mutation in the cardiac ryanodine receptor gene (RyR2) and their subsequent differentiation into cardiomyocytes (CMs). Whole-cell patch-clamp and intracellular electrical recordings of spontaneously beating cells revealed the presence of delayed afterdepolarizations (DADs) in CPVT-CMs, both in resting conditions and after ß-adrenergic stimulation, resembling the cardiac phenotype of the patients. Furthermore, treatment with KN-93 (2-[N-(2-hydroxyethyl)]-N-(4methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine), an antiarrhythmic drug that inhibits Ca(2+)/calmodulin-dependent serine-threonine protein kinase II (CaMKII), drastically reduced the presence of DADs in CVPT-CMs, rescuing the arrhythmic phenotype induced by catecholaminergic stress. In addition, intracellular calcium transient measurements on 3D beating clusters by fast resolution optical mapping showed that CPVT clusters developed multiple calcium transients, whereas in the wild-type clusters, only single initiations were detected. Such instability is aggravated in the presence of isoproterenol and is attenuated by KN-93. As seen in our RyR2 knock-in CPVT mice, the antiarrhythmic effect of KN-93 is confirmed in these human iPSC-derived cardiac cells, supporting the role of this in vitro system for drug screening and optimization of clinical treatment strategies. |
| File Format | HTM / HTML |
| e-ISSN | 20414889 |
| DOI | 10.1038/cddis.2013.369 |
| Journal | Cell Death and Disease |
| Volume Number | 4 |
| Language | English |
| Publisher | Nature Publishing Group |
| Publisher Date | 2013-10-10 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Research Support, Non-u.s. Gov't Calcium Ryanodine Receptor Calcium Release Channel Cytology Child, Preschool Molecular Sequence Data Arrhythmias, Cardiac Antagonists & Inhibitors Tachycardia, Ventricular Hek293 Cells Genetics Cell Differentiation Calcium-calmodulin-dependent Protein Kinase Type 2 Myocytes, Cardiac Complications Drug Therapy Pharmacology Metabolism Drug Effects Therapeutic Use Receptors, Adrenergic, Beta Discipline Cell Biology Pathology Protein Kinase Inhibitors Phenotype Animals Sulfonamides Pedigree Adolescent Benzylamines Mice Enzymology Induced Pluripotent Stem Cells |
| Content Type | Text |
| Resource Type | Case study Article |
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