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

BackgroundCatecholaminergic 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 c...

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Autores principales:	Bin Liu, Shane D. Walton, Hsiang‐Ting Ho, Andriy E. Belevych, Svetlana B. Tikunova, Ingrid Bonilla, Vikram Shettigar, Bjorn C. Knollmann, Silvia G. Priori, Pompeo Volpe, Przemysław B. Radwański, Jonathan P. Davis, Sándor Györke
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2018
Materias:	arrhythmia (mechanisms) calcium channel calcium signaling calmodulin gene therapy Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/17b2d1203c6b4fb18ec412e87dd32e52
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spelling	oai:doaj.org-article:17b2d1203c6b4fb18ec412e87dd32e522021-11-12T17:01:48ZGene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia10.1161/JAHA.117.0081552047-9980https://doaj.org/article/17b2d1203c6b4fb18ec412e87dd32e522018-05-01T00:00:00Zhttps://www.ahajournals.org/doi/10.1161/JAHA.117.008155https://doaj.org/toc/2047-9980BackgroundCatecholaminergic 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 ResultsTo 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. ConclusionsOur 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.Bin LiuShane D. WaltonHsiang‐Ting HoAndriy E. BelevychSvetlana B. TikunovaIngrid BonillaVikram ShettigarBjorn C. KnollmannSilvia G. PrioriPompeo VolpePrzemysław B. RadwańskiJonathan P. DavisSándor GyörkeWileyarticlearrhythmia (mechanisms)calcium channelcalcium signalingcalmodulingene therapyDiseases of the circulatory (Cardiovascular) systemRC666-701ENJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 7, Iss 10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	arrhythmia (mechanisms) calcium channel calcium signaling calmodulin gene therapy Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	arrhythmia (mechanisms) calcium channel calcium signaling calmodulin gene therapy Diseases of the circulatory (Cardiovascular) system RC666-701 Bin Liu Shane D. Walton Hsiang‐Ting Ho Andriy E. Belevych Svetlana B. Tikunova Ingrid Bonilla Vikram Shettigar Bjorn C. Knollmann Silvia G. Priori Pompeo Volpe Przemysław B. Radwański Jonathan P. Davis Sándor Györke Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
description	BackgroundCatecholaminergic 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 ResultsTo 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. ConclusionsOur 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.
format	article
author	Bin Liu Shane D. Walton Hsiang‐Ting Ho Andriy E. Belevych Svetlana B. Tikunova Ingrid Bonilla Vikram Shettigar Bjorn C. Knollmann Silvia G. Priori Pompeo Volpe Przemysław B. Radwański Jonathan P. Davis Sándor Györke
author_facet	Bin Liu Shane D. Walton Hsiang‐Ting Ho Andriy E. Belevych Svetlana B. Tikunova Ingrid Bonilla Vikram Shettigar Bjorn C. Knollmann Silvia G. Priori Pompeo Volpe Przemysław B. Radwański Jonathan P. Davis Sándor Györke
author_sort	Bin Liu
title	Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
title_short	Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
title_full	Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
title_fullStr	Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
title_full_unstemmed	Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
title_sort	gene transfer of engineered calmodulin alleviates ventricular arrhythmias in a calsequestrin‐associated mouse model of catecholaminergic polymorphic ventricular tachycardia
publisher	Wiley
publishDate	2018
url	https://doaj.org/article/17b2d1203c6b4fb18ec412e87dd32e52
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Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

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