Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.

Autor: Liu B; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH.; Department of Biological Sciences, Mississippi State University, Starkville, MI., Walton SD; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH., Ho HT; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH., Belevych AE; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH., Tikunova SB; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH., Bonilla I; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH., Shettigar V; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH., Knollmann BC; Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Vanderbilt, TN., Priori SG; Division of Cardiology and Molecular Cardiology, Maugeri Foundation-University of Pavia, Italy., Volpe P; Department of Biomedical Sciences, University of Padova, Italy., Radwański PB; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH., Davis JP; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH davis.812@osu.edu sandor.gyorke@osumc.edu., Györke S; Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH davis.812@osu.edu sandor.gyorke@osumc.edu.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2018 May 02; Vol. 7 (10). Date of Electronic Publication: 2018 May 02.
DOI: 10.1161/JAHA.117.008155
Abstrakt: Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral-mediated delivery to alleviate arrhythmias in non-CaM-related CPVT.
Methods and Results: To that end, we have designed a CaM protein (GSH-M37Q; dubbed as therapeutic CaM or T-CaM) that exhibited a slowed N-terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from CPVT mice carrying the CASQ2 mutation R33Q. This T-CaM was introduced to the heart of R33Q mice through recombinant adeno-associated viral vector serotype 9. Eight weeks postinfection, we performed confocal microscopy to assess Ca handling and recorded surface ECGs to assess susceptibility to arrhythmias in vivo. During catecholamine stimulation with isoproterenol, T-CaM reduced isoproterenol-promoted diastolic Ca waves in isolated CPVT cardiomyocytes. Importantly, T-CaM exposure abolished ventricular tachycardia in CPVT mice challenged with catecholamines.
Conclusions: Our results suggest that gene transfer of T-CaM by adeno-associated viral vector serotype 9 improves myocyte Ca handling and alleviates arrhythmias in a calsequestrin-associated CPVT model, thus supporting the potential of a CaM-based antiarrhythmic approach as a therapeutic avenue for genetically distinct forms of CPVT.
(© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)
Databáze: MEDLINE
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