Functional abnormalities in iPSC‐derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations
| Autor: | Michael Eldar, Lili Barad, Liron Eldor, Atara Novak, Binyamin Eisen, Michael Arad, Ofer Binah, Mihaela Gherghiceanu, Joseph Itskovitz-Eldor, Irina Reiter, Avraham Lorber |
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| Rok vydání: | 2015 |
| Předmět: |
Inotrope
medicine.medical_specialty Lusitropy Genotyping Techniques Induced Pluripotent Stem Cells Molecular Sequence Data cardiomyocytes Biology medicine.disease_cause Calsequestrin Catecholaminergic polymorphic ventricular tachycardia Sudden death Ryanodine receptor 2 Caffeine Internal medicine catacholaminergic polymorphic ventricular tachycardia Ca2+ transients medicine Humans Myocytes Cardiac Calcium Signaling Mutation Base Sequence Ryanodine receptor Isoproterenol Cell Differentiation Ryanodine Receptor Calcium Release Channel Original Articles Cell Biology medicine.disease Sarcoplasmic Reticulum Endocrinology Tachycardia Ventricular cardiovascular system Molecular Medicine arrhythmias |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| Popis: | Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by syncope and sudden death occurring during exercise or acute emotion. CPVT is caused by abnormal intracellular Ca(2+) handling resulting from mutations in the RyR2 or CASQ2 genes. Because CASQ2 and RyR2 are involved in different aspects of the excitation-contraction coupling process, we hypothesized that these mutations are associated with different functional and intracellular Ca(²+) abnormalities. To test the hypothesis we generated induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CM) from CPVT1 and CPVT2 patients carrying the RyR2(R420Q) and CASQ2(D307H) mutations, respectively, and investigated in CPVT1 and CPVT2 iPSC-CM (compared to control): (i) The ultrastructural features; (ii) the effects of isoproterenol, caffeine and ryanodine on the [Ca(2+) ]i transient characteristics. Our major findings were: (i) Ultrastructurally, CASQ2 and RyR2 mutated cardiomyocytes were less developed than control cardiomyocytes. (ii) While in control iPSC-CM isoproterenol caused positive inotropic and lusitropic effects, in the mutated cardiomyocytes isoproterenol was either ineffective, caused arrhythmias, or markedly increased diastolic [Ca(2+) ]i . Importantly, positive inotropic and lusitropic effects were not induced in mutated cardiomyocytes. (iii) The effects of caffeine and ryanodine in mutated cardiomyocytes differed from control cardiomyocytes. Our results show that iPSC-CM are useful for investigating the similarities/differences in the pathophysiological consequences of RyR2 versus CASQ2 mutations underlying CPVT1 and CPVT2 syndromes. |
| Databáze: | OpenAIRE |
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