The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts

Sarcoplasmic reticulum (SR) Ca2+ cycling is governed by the cardiac ryanodine receptor (RyR2) and SR Ca2+-ATPase (SERCA2a). Abnormal SR Ca2+ cycling is thought to be the primary cause of Ca2+ alternans that can elicit ventricular arrhythmias and sudden cardiac arrest. Although alterations in either...

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Autores: Sun, Bo, Wei, Jinhong, Zhong, Xiaowei, Vallmitjana Lees, Alexander, Benítez Iglesias, Raúl|||0000-0002-8782-9406
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/125271
Acceso en línea:https://hdl.handle.net/2117/125271
https://dx.doi.org/10.1074/jbc.RA118.003760
Access Level:acceso abierto
Palabra clave:Ventricular tachycardia
Calcium
Ryanodine--Receptors
Endoplasmic reticulum
Ventricular tachyarrhythmia
Ca2+ alternans
Ca2+ release refractoriness
phospholamban
intact heart imaging
calcium intracellular release
calcium
calcium ATPase
ryanodine receptor
sarcoplasmic reticulum (SR)
calcium imaging
endoplasmic reticulum (ER)
Calci
Taquicàrdia ventricular
Àrees temàtiques de la UPC::Enginyeria biomèdica
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spelling The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse heartsSun, BoWei, JinhongZhong, XiaoweiVallmitjana Lees, AlexanderBenítez Iglesias, Raúl|||0000-0002-8782-9406Ventricular tachycardiaCalciumRyanodine--ReceptorsEndoplasmic reticulumVentricular tachyarrhythmiaCa2+ alternansCa2+ release refractorinessphospholambanintact heart imagingcalcium intracellular releasecalciumcalcium ATPaseryanodine receptorsarcoplasmic reticulum (SR)calcium imagingendoplasmic reticulum (ER)CalciTaquicàrdia ventricularÀrees temàtiques de la UPC::Enginyeria biomèdicaSarcoplasmic reticulum (SR) Ca2+ cycling is governed by the cardiac ryanodine receptor (RyR2) and SR Ca2+-ATPase (SERCA2a). Abnormal SR Ca2+ cycling is thought to be the primary cause of Ca2+ alternans that can elicit ventricular arrhythmias and sudden cardiac arrest. Although alterations in either RyR2 or SERCA2a function are expected to affect SR Ca2+ cycling, whether and to what extent altered RyR2 or SERCA2a function affects Ca2+ alternans is unclear. Here we employed a gain-of-function RyR2 variant (R4496C) and the phospholamban-knockout (PLB-KO) mouse model to assess the effect of genetically enhanced RyR2 or SERCA2a function on Ca2+ alternans. Confocal Ca2+ imaging revealed that RyR2-R4496C shortened SR Ca2+ release refractoriness and markedly suppressed rapid pacing-induced Ca2+ alternans. Interestingly, despite enhancing RyR2 function, intact RyR2-R4496C hearts exhibited no detectable spontaneous SR Ca2+ release events during pacing. Unlike for RyR2, enhancing SERCA2a function by ablating PLB exerted a relatively minor effect on Ca2+ alternans in intact hearts expressing RyR2 wildtype or a loss-of-function RyR2 variant, E4872Q, that promotes Ca2+ alternans. Furthermore, partial SERCA2a inhibition with 3 µM 2,5-di-tert-butylhydroquinone (tBHQ) also had little impact on Ca2+ alternans, while strong SERCA2a inhibition with 10 µM tBHQ markedly reduced the amplitude of Ca2+ transients and suppressed Ca2+ alternans in intact hearts. Our results demonstrate that enhanced RyR2 function suppresses Ca2+ alternans in the absence of spontaneous Ca2+ release and that RyR2, but not SERCA2a, is a key determinant of Ca2+ alternans in intact working hearts, making RyR2 an important therapeutic target for cardiac alternans.Peer Reviewed20182018-07-0920182018-11-30journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/125271https://dx.doi.org/10.1074/jbc.RA118.003760reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivs 3.0 Spainhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/1252712026-05-27T15:37:01Z
dc.title.none.fl_str_mv The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
title The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
spellingShingle The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
Sun, Bo
Ventricular tachycardia
Calcium
Ryanodine--Receptors
Endoplasmic reticulum
Ventricular tachyarrhythmia
Ca2+ alternans
Ca2+ release refractoriness
phospholamban
intact heart imaging
calcium intracellular release
calcium
calcium ATPase
ryanodine receptor
sarcoplasmic reticulum (SR)
calcium imaging
endoplasmic reticulum (ER)
Calci
Taquicàrdia ventricular
Àrees temàtiques de la UPC::Enginyeria biomèdica
title_short The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
title_full The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
title_fullStr The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
title_full_unstemmed The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
title_sort The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2-ATPase, is a major determinant of Ca2 alternans in intact mouse hearts
dc.creator.none.fl_str_mv Sun, Bo
Wei, Jinhong
Zhong, Xiaowei
Vallmitjana Lees, Alexander
Benítez Iglesias, Raúl|||0000-0002-8782-9406
author Sun, Bo
author_facet Sun, Bo
Wei, Jinhong
Zhong, Xiaowei
Vallmitjana Lees, Alexander
Benítez Iglesias, Raúl|||0000-0002-8782-9406
author_role author
author2 Wei, Jinhong
Zhong, Xiaowei
Vallmitjana Lees, Alexander
Benítez Iglesias, Raúl|||0000-0002-8782-9406
author2_role author
author
author
author
dc.subject.none.fl_str_mv Ventricular tachycardia
Calcium
Ryanodine--Receptors
Endoplasmic reticulum
Ventricular tachyarrhythmia
Ca2+ alternans
Ca2+ release refractoriness
phospholamban
intact heart imaging
calcium intracellular release
calcium
calcium ATPase
ryanodine receptor
sarcoplasmic reticulum (SR)
calcium imaging
endoplasmic reticulum (ER)
Calci
Taquicàrdia ventricular
Àrees temàtiques de la UPC::Enginyeria biomèdica
topic Ventricular tachycardia
Calcium
Ryanodine--Receptors
Endoplasmic reticulum
Ventricular tachyarrhythmia
Ca2+ alternans
Ca2+ release refractoriness
phospholamban
intact heart imaging
calcium intracellular release
calcium
calcium ATPase
ryanodine receptor
sarcoplasmic reticulum (SR)
calcium imaging
endoplasmic reticulum (ER)
Calci
Taquicàrdia ventricular
Àrees temàtiques de la UPC::Enginyeria biomèdica
description Sarcoplasmic reticulum (SR) Ca2+ cycling is governed by the cardiac ryanodine receptor (RyR2) and SR Ca2+-ATPase (SERCA2a). Abnormal SR Ca2+ cycling is thought to be the primary cause of Ca2+ alternans that can elicit ventricular arrhythmias and sudden cardiac arrest. Although alterations in either RyR2 or SERCA2a function are expected to affect SR Ca2+ cycling, whether and to what extent altered RyR2 or SERCA2a function affects Ca2+ alternans is unclear. Here we employed a gain-of-function RyR2 variant (R4496C) and the phospholamban-knockout (PLB-KO) mouse model to assess the effect of genetically enhanced RyR2 or SERCA2a function on Ca2+ alternans. Confocal Ca2+ imaging revealed that RyR2-R4496C shortened SR Ca2+ release refractoriness and markedly suppressed rapid pacing-induced Ca2+ alternans. Interestingly, despite enhancing RyR2 function, intact RyR2-R4496C hearts exhibited no detectable spontaneous SR Ca2+ release events during pacing. Unlike for RyR2, enhancing SERCA2a function by ablating PLB exerted a relatively minor effect on Ca2+ alternans in intact hearts expressing RyR2 wildtype or a loss-of-function RyR2 variant, E4872Q, that promotes Ca2+ alternans. Furthermore, partial SERCA2a inhibition with 3 µM 2,5-di-tert-butylhydroquinone (tBHQ) also had little impact on Ca2+ alternans, while strong SERCA2a inhibition with 10 µM tBHQ markedly reduced the amplitude of Ca2+ transients and suppressed Ca2+ alternans in intact hearts. Our results demonstrate that enhanced RyR2 function suppresses Ca2+ alternans in the absence of spontaneous Ca2+ release and that RyR2, but not SERCA2a, is a key determinant of Ca2+ alternans in intact working hearts, making RyR2 an important therapeutic target for cardiac alternans.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018-07-09
2018
2018-11-30
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/125271
https://dx.doi.org/10.1074/jbc.RA118.003760
url https://hdl.handle.net/2117/125271
https://dx.doi.org/10.1074/jbc.RA118.003760
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivs 3.0 Spain
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivs 3.0 Spain
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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