Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction

Background: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/–, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has...

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Autores: Ni, Mingke, Li, Yanhui, Wei, Jinhong, Song, Zhenpeng, Wang, Hui, Yao, Jinjing, Chen, Yong-Xiang, Belke, Darrell, Estillore, John Paul, Wang, Ruiwu, Vallmitjana Lees, Alexander, Benítez Iglesias, Raúl|||0000-0002-8782-9406, Hove Madsen, Leif, Feng, Wei, Chen, Ju
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/398769
Acesso em linha:https://hdl.handle.net/2117/398769
https://dx.doi.org/10.1161/CIRCRESAHA.123.322504
Access Level:acceso abierto
Palavra-chave:Electronics in cardiology
Electrònica en cardiologia
Àrees temàtiques de la UPC::Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologia
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spelling Increased Ca2+ transient underlies RyR2-related left ventricular noncompactionNi, MingkeLi, YanhuiWei, JinhongSong, ZhenpengWang, HuiYao, JinjingChen, Yong-XiangBelke, DarrellEstillore, John PaulWang, RuiwuVallmitjana Lees, AlexanderBenítez Iglesias, Raúl|||0000-0002-8782-9406Hove Madsen, LeifFeng, WeiChen, JuElectronics in cardiologyElectrònica en cardiologiaÀrees temàtiques de la UPC::Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologiaBackground: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/–, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/– loss-of-function mutation on cardiac structure and function. Methods: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/– mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/– mutation. Results: As in humans, RyR2-I4855M+/– mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/– mice were highly susceptible to electrical stimulation–induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/– mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/– mutation abolished sarcoplasmic reticulum store overload–induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/– mutant compared with wild type. Conclusions: The RyR2-I4855M+/– mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/– mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.Peer Reviewed20232023-07-0720232023-12-22journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/398769https://dx.doi.org/10.1161/CIRCRESAHA.123.322504reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/3987692026-05-27T15:37:01Z
dc.title.none.fl_str_mv Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
title Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
spellingShingle Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
Ni, Mingke
Electronics in cardiology
Electrònica en cardiologia
Àrees temàtiques de la UPC::Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologia
title_short Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
title_full Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
title_fullStr Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
title_full_unstemmed Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
title_sort Increased Ca2+ transient underlies RyR2-related left ventricular noncompaction
dc.creator.none.fl_str_mv Ni, Mingke
Li, Yanhui
Wei, Jinhong
Song, Zhenpeng
Wang, Hui
Yao, Jinjing
Chen, Yong-Xiang
Belke, Darrell
Estillore, John Paul
Wang, Ruiwu
Vallmitjana Lees, Alexander
Benítez Iglesias, Raúl|||0000-0002-8782-9406
Hove Madsen, Leif
Feng, Wei
Chen, Ju
author Ni, Mingke
author_facet Ni, Mingke
Li, Yanhui
Wei, Jinhong
Song, Zhenpeng
Wang, Hui
Yao, Jinjing
Chen, Yong-Xiang
Belke, Darrell
Estillore, John Paul
Wang, Ruiwu
Vallmitjana Lees, Alexander
Benítez Iglesias, Raúl|||0000-0002-8782-9406
Hove Madsen, Leif
Feng, Wei
Chen, Ju
author_role author
author2 Li, Yanhui
Wei, Jinhong
Song, Zhenpeng
Wang, Hui
Yao, Jinjing
Chen, Yong-Xiang
Belke, Darrell
Estillore, John Paul
Wang, Ruiwu
Vallmitjana Lees, Alexander
Benítez Iglesias, Raúl|||0000-0002-8782-9406
Hove Madsen, Leif
Feng, Wei
Chen, Ju
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Electronics in cardiology
Electrònica en cardiologia
Àrees temàtiques de la UPC::Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologia
topic Electronics in cardiology
Electrònica en cardiologia
Àrees temàtiques de la UPC::Enginyeria biomèdica::Electrònica biomèdica::Electrònica en cardiologia
description Background: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/–, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/– loss-of-function mutation on cardiac structure and function. Methods: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/– mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/– mutation. Results: As in humans, RyR2-I4855M+/– mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/– mice were highly susceptible to electrical stimulation–induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/– mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/– mutation abolished sarcoplasmic reticulum store overload–induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/– mutant compared with wild type. Conclusions: The RyR2-I4855M+/– mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/– mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-07-07
2023
2023-12-22
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/398769
https://dx.doi.org/10.1161/CIRCRESAHA.123.322504
url https://hdl.handle.net/2117/398769
https://dx.doi.org/10.1161/CIRCRESAHA.123.322504
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-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
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-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
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
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