Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias
| Autor: | Carlo Napolitano, Alberto Auricchio, Simona Boncompagni, Feliciano Protasi, Pompeo Volpe, José Everardo Avelino-Cruz, Laura Villani, Silvia G. Priori, Marco Denegri, Stefano Andrea De Simone |
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| Přispěvatelé: | Denegri, M, Avelino Cruz, Je, Boncompagni, S, De Simone, Sa, Auricchio, Alberto, Villani, L, Volpe, P, Protasi, F, Napolitano, C, Priori, Sg |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Physiology Heart Ventricles Muscle Proteins Biology Calsequestrin Catecholaminergic polymorphic ventricular tachycardia Sudden death Ryanodine receptor 2 Mixed Function Oxygenases Electrocardiography Mice Mutant protein Internal medicine medicine Animals Myocytes Cardiac Cells Cultured Mice Knockout Ryanodine receptor Calcium-Binding Proteins Genetic transfer Gene Transfer Techniques Membrane Proteins Arrhythmias Cardiac Ryanodine Receptor Calcium Release Channel Dependovirus medicine.disease Cell biology Mice Inbred C57BL Disease Models Animal Phenotype Endocrinology Triadin Mutation Tachycardia Ventricular Female Carrier Proteins Cardiology and Cardiovascular Medicine |
| Popis: | Rationale: Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum. Objective: We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2. Methods and Results: We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias. Conclusions: We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application. |
| Databáze: | OpenAIRE |
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