Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart

Autores
Bell, James R.; Raaijmakers, Antonia J.A.; Curl, Claire L.; Reichelt, Melissa E.; Harding, Tristan W.; Bei, Aier; Ng, Dominic C.H.; Erickson, Jeffrey R.; Vila Petroff, Martin Gerarde; Harrap, Stephen B.; Delbridge, Lea M.D.
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
BACKGROUND: Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca(2+)/calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts. METHODS AND RESULTS: Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca(2+)-challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 ± 18 vs 548 ± 9, s, p<0.05), yet had augmented P-CaMKII (2.69 ± 0.30 vs 1.50 ± 0.14, rel. units, p<0.05) and downstream phosphorylation of phospholamban (1.71 ± 0.42 vs 0.90 ± 0.10, p<0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca(2+)-handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIδB and CaMKIIδC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively. CONCLUSIONS: This study provides new mechanistic evidence that CaMKIIδ splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIδB(Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid.
Fil: Bell, James R.. The University Of Melbourne; Australia
Fil: Raaijmakers, Antonia J.A.. The University Of Melbourne; Australia
Fil: Curl, Claire L.. The University Of Melbourne; Australia
Fil: Reichelt, Melissa E.. The University Of Melbourne; Australia
Fil: Harding, Tristan W.. The University Of Melbourne; Australia
Fil: Bei, Aier. The University Of Melbourne; Australia
Fil: Ng, Dominic C.H.. The University Of Melbourne; Australia
Fil: Erickson, Jeffrey R.. University Of Otago; Nueva Zelanda
Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina
Fil: Harrap, Stephen B.. The University Of Melbourne; Australia
Fil: Delbridge, Lea M.D.. The University Of Melbourne; Australia
Materia
Ca(2+) Regulation
Cardiac Myocytes
Ischemia/Reperfusion
Sex-Specific
Ventricular Arrhythmia
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/12023
Acceder
id CONICETDig_51ea32199512bcc4a3ad5a96c26368c8
oai_identifier_str oai:ri.conicet.gov.ar:11336/12023
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heartBell, James R.Raaijmakers, Antonia J.A.Curl, Claire L.Reichelt, Melissa E.Harding, Tristan W.Bei, AierNg, Dominic C.H.Erickson, Jeffrey R.Vila Petroff, Martin GerardeHarrap, Stephen B.Delbridge, Lea M.D.Ca(2+) RegulationCardiac MyocytesIschemia/ReperfusionSex-SpecificVentricular Arrhythmiahttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3BACKGROUND: Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca(2+)/calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts. METHODS AND RESULTS: Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca(2+)-challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 ± 18 vs 548 ± 9, s, p<0.05), yet had augmented P-CaMKII (2.69 ± 0.30 vs 1.50 ± 0.14, rel. units, p<0.05) and downstream phosphorylation of phospholamban (1.71 ± 0.42 vs 0.90 ± 0.10, p<0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca(2+)-handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIδB and CaMKIIδC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively. CONCLUSIONS: This study provides new mechanistic evidence that CaMKIIδ splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIδB(Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid.Fil: Bell, James R.. The University Of Melbourne; AustraliaFil: Raaijmakers, Antonia J.A.. The University Of Melbourne; AustraliaFil: Curl, Claire L.. The University Of Melbourne; AustraliaFil: Reichelt, Melissa E.. The University Of Melbourne; AustraliaFil: Harding, Tristan W.. The University Of Melbourne; AustraliaFil: Bei, Aier. The University Of Melbourne; AustraliaFil: Ng, Dominic C.H.. The University Of Melbourne; AustraliaFil: Erickson, Jeffrey R.. University Of Otago; Nueva ZelandaFil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: Harrap, Stephen B.. The University Of Melbourne; AustraliaFil: Delbridge, Lea M.D.. The University Of Melbourne; AustraliaElsevier Ireland2015-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/12023Bell, James R.; Raaijmakers, Antonia J.A.; Curl, Claire L.; Reichelt, Melissa E.; Harding, Tristan W.; et al.; Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart; Elsevier Ireland; International Journal Of Cardiology; 181; 2-2015; 288-2960167-5273enginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ijcard.2014.11.159info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0167527314023407info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:44:50Zoai:ri.conicet.gov.ar:11336/12023instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:44:50.584CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
title Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
spellingShingle Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
Bell, James R.
Ca(2+) Regulation
Cardiac Myocytes
Ischemia/Reperfusion
Sex-Specific
Ventricular Arrhythmia
title_short Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
title_full Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
title_fullStr Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
title_full_unstemmed Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
title_sort Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart
dc.creator.none.fl_str_mv Bell, James R.
Raaijmakers, Antonia J.A.
Curl, Claire L.
Reichelt, Melissa E.
Harding, Tristan W.
Bei, Aier
Ng, Dominic C.H.
Erickson, Jeffrey R.
Vila Petroff, Martin Gerarde
Harrap, Stephen B.
Delbridge, Lea M.D.
author Bell, James R.
author_facet Bell, James R.
Raaijmakers, Antonia J.A.
Curl, Claire L.
Reichelt, Melissa E.
Harding, Tristan W.
Bei, Aier
Ng, Dominic C.H.
Erickson, Jeffrey R.
Vila Petroff, Martin Gerarde
Harrap, Stephen B.
Delbridge, Lea M.D.
author_role author
author2 Raaijmakers, Antonia J.A.
Curl, Claire L.
Reichelt, Melissa E.
Harding, Tristan W.
Bei, Aier
Ng, Dominic C.H.
Erickson, Jeffrey R.
Vila Petroff, Martin Gerarde
Harrap, Stephen B.
Delbridge, Lea M.D.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ca(2+) Regulation
Cardiac Myocytes
Ischemia/Reperfusion
Sex-Specific
Ventricular Arrhythmia
topic Ca(2+) Regulation
Cardiac Myocytes
Ischemia/Reperfusion
Sex-Specific
Ventricular Arrhythmia
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv BACKGROUND: Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca(2+)/calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts. METHODS AND RESULTS: Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca(2+)-challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 ± 18 vs 548 ± 9, s, p<0.05), yet had augmented P-CaMKII (2.69 ± 0.30 vs 1.50 ± 0.14, rel. units, p<0.05) and downstream phosphorylation of phospholamban (1.71 ± 0.42 vs 0.90 ± 0.10, p<0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca(2+)-handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIδB and CaMKIIδC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively. CONCLUSIONS: This study provides new mechanistic evidence that CaMKIIδ splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIδB(Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid.
Fil: Bell, James R.. The University Of Melbourne; Australia
Fil: Raaijmakers, Antonia J.A.. The University Of Melbourne; Australia
Fil: Curl, Claire L.. The University Of Melbourne; Australia
Fil: Reichelt, Melissa E.. The University Of Melbourne; Australia
Fil: Harding, Tristan W.. The University Of Melbourne; Australia
Fil: Bei, Aier. The University Of Melbourne; Australia
Fil: Ng, Dominic C.H.. The University Of Melbourne; Australia
Fil: Erickson, Jeffrey R.. University Of Otago; Nueva Zelanda
Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina
Fil: Harrap, Stephen B.. The University Of Melbourne; Australia
Fil: Delbridge, Lea M.D.. The University Of Melbourne; Australia
description BACKGROUND: Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca(2+)/calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts. METHODS AND RESULTS: Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca(2+)-challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 ± 18 vs 548 ± 9, s, p<0.05), yet had augmented P-CaMKII (2.69 ± 0.30 vs 1.50 ± 0.14, rel. units, p<0.05) and downstream phosphorylation of phospholamban (1.71 ± 0.42 vs 0.90 ± 0.10, p<0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca(2+)-handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIδB and CaMKIIδC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively. CONCLUSIONS: This study provides new mechanistic evidence that CaMKIIδ splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIδB(Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid.
publishDate 2015
dc.date.none.fl_str_mv 2015-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/12023
Bell, James R.; Raaijmakers, Antonia J.A.; Curl, Claire L.; Reichelt, Melissa E.; Harding, Tristan W.; et al.; Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart; Elsevier Ireland; International Journal Of Cardiology; 181; 2-2015; 288-296
0167-5273
url http://hdl.handle.net/11336/12023
identifier_str_mv Bell, James R.; Raaijmakers, Antonia J.A.; Curl, Claire L.; Reichelt, Melissa E.; Harding, Tristan W.; et al.; Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart; Elsevier Ireland; International Journal Of Cardiology; 181; 2-2015; 288-296
0167-5273
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ijcard.2014.11.159
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0167527314023407
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Ireland
publisher.none.fl_str_mv Elsevier Ireland
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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