Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

Autores
Federico, Marilén; Portiansky, Enrique Leo; Sommese, Leandro Matías; Alvarado, Francisco J.; Blanco, Paula Graciela; Zanuzzi, Carolina Natalia; Dedman, John; Kaetzel, Marcia; Wehrens, Xander H. T.; Mattiazzi, Ramona Alicia; Palomeque, Julieta
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The impact of cardiac apoptosis in pre‐diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose‐rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca2+/calmodulin‐protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca2+ leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre‐diabetes. We generated a pre‐diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca2+ spontaneous events in the absence of SR Ca2+ load alterations vs. control‐diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [3H]ryanodine binding and CaMKII phosphorylation of RyR2‐S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia‐induced alterations. FRD also evoked cardiac apoptosis in WT mice vs. CD‐WT mice. Co‐treatment with the reactive oxygen species scavenger Tempol prevented FRD‐induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD‐SR‐AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR–mitochondrial distance vs. CD‐WT hearts. This remodelling was prevented in AC3I mice, with cardiac‐targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca2+ leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre‐diabetic heart. The FRD‐induced decrease in SR–mitochondrial distance is likely to additionally favour Ca2+ transit between the two organelles.
Fil: Federico, Marilén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Portiansky, Enrique Leo. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina
Fil: Sommese, Leandro Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Alvarado, Francisco J.. University of Michigan; Estados Unidos
Fil: Blanco, Paula Graciela. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina
Fil: Zanuzzi, Carolina Natalia. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina
Fil: Dedman, John. University of Cincinnati; Estados Unidos
Fil: Kaetzel, Marcia. University of Cincinnati; Estados Unidos
Fil: Wehrens, Xander H. T.. Baylor Coleege of Medicine. Cardiovascular Research Institute; Estados Unidos
Fil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Palomeque, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Materia
Apoptosis
Camkii
Diabetes
Mitochondria
Sarcoplasmic Reticulum
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:11336/49486
Acceder
id CONICETDig_9b08f1be19ecfda6b62e98b37fd9da93
oai_identifier_str oai:ri.conicet.gov.ar:11336/49486
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose toleranceFederico, MarilénPortiansky, Enrique LeoSommese, Leandro MatíasAlvarado, Francisco J.Blanco, Paula GracielaZanuzzi, Carolina NataliaDedman, JohnKaetzel, MarciaWehrens, Xander H. T.Mattiazzi, Ramona AliciaPalomeque, JulietaApoptosisCamkiiDiabetesMitochondriaSarcoplasmic Reticulumhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3https://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3https://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3The impact of cardiac apoptosis in pre‐diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose‐rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca2+/calmodulin‐protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca2+ leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre‐diabetes. We generated a pre‐diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca2+ spontaneous events in the absence of SR Ca2+ load alterations vs. control‐diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [3H]ryanodine binding and CaMKII phosphorylation of RyR2‐S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia‐induced alterations. FRD also evoked cardiac apoptosis in WT mice vs. CD‐WT mice. Co‐treatment with the reactive oxygen species scavenger Tempol prevented FRD‐induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD‐SR‐AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR–mitochondrial distance vs. CD‐WT hearts. This remodelling was prevented in AC3I mice, with cardiac‐targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca2+ leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre‐diabetic heart. The FRD‐induced decrease in SR–mitochondrial distance is likely to additionally favour Ca2+ transit between the two organelles.Fil: Federico, Marilén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Portiansky, Enrique Leo. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; ArgentinaFil: Sommese, Leandro Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Alvarado, Francisco J.. University of Michigan; Estados UnidosFil: Blanco, Paula Graciela. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; ArgentinaFil: Zanuzzi, Carolina Natalia. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; ArgentinaFil: Dedman, John. University of Cincinnati; Estados UnidosFil: Kaetzel, Marcia. University of Cincinnati; Estados UnidosFil: Wehrens, Xander H. T.. Baylor Coleege of Medicine. Cardiovascular Research Institute; Estados UnidosFil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Palomeque, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaThe Phisiological Society2017-01-20info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/49486Federico, Marilén; Portiansky, Enrique Leo; Sommese, Leandro Matías; Alvarado, Francisco J.; Blanco, Paula Graciela; et al.; Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance; The Phisiological Society; The Journal Of Physiology; 595; 12; 20-1-2017; 4089-41080022-37511469-7793CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP273714info:eu-repo/semantics/altIdentifier/doi/10.1113/JP273714info:eu-repo/semantics/altIdentifier/pmid/28105734info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471423/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:35:29Zoai:ri.conicet.gov.ar:11336/49486instacron: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 10:35:29.62CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
spellingShingle Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
Federico, Marilén
Apoptosis
Camkii
Diabetes
Mitochondria
Sarcoplasmic Reticulum
title_short Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_full Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_fullStr Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_full_unstemmed Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
title_sort Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance
dc.creator.none.fl_str_mv Federico, Marilén
Portiansky, Enrique Leo
Sommese, Leandro Matías
Alvarado, Francisco J.
Blanco, Paula Graciela
Zanuzzi, Carolina Natalia
Dedman, John
Kaetzel, Marcia
Wehrens, Xander H. T.
Mattiazzi, Ramona Alicia
Palomeque, Julieta
author Federico, Marilén
author_facet Federico, Marilén
Portiansky, Enrique Leo
Sommese, Leandro Matías
Alvarado, Francisco J.
Blanco, Paula Graciela
Zanuzzi, Carolina Natalia
Dedman, John
Kaetzel, Marcia
Wehrens, Xander H. T.
Mattiazzi, Ramona Alicia
Palomeque, Julieta
author_role author
author2 Portiansky, Enrique Leo
Sommese, Leandro Matías
Alvarado, Francisco J.
Blanco, Paula Graciela
Zanuzzi, Carolina Natalia
Dedman, John
Kaetzel, Marcia
Wehrens, Xander H. T.
Mattiazzi, Ramona Alicia
Palomeque, Julieta
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Apoptosis
Camkii
Diabetes
Mitochondria
Sarcoplasmic Reticulum
topic Apoptosis
Camkii
Diabetes
Mitochondria
Sarcoplasmic Reticulum
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The impact of cardiac apoptosis in pre‐diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose‐rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca2+/calmodulin‐protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca2+ leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre‐diabetes. We generated a pre‐diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca2+ spontaneous events in the absence of SR Ca2+ load alterations vs. control‐diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [3H]ryanodine binding and CaMKII phosphorylation of RyR2‐S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia‐induced alterations. FRD also evoked cardiac apoptosis in WT mice vs. CD‐WT mice. Co‐treatment with the reactive oxygen species scavenger Tempol prevented FRD‐induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD‐SR‐AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR–mitochondrial distance vs. CD‐WT hearts. This remodelling was prevented in AC3I mice, with cardiac‐targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca2+ leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre‐diabetic heart. The FRD‐induced decrease in SR–mitochondrial distance is likely to additionally favour Ca2+ transit between the two organelles.
Fil: Federico, Marilén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Portiansky, Enrique Leo. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina
Fil: Sommese, Leandro Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Alvarado, Francisco J.. University of Michigan; Estados Unidos
Fil: Blanco, Paula Graciela. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina
Fil: Zanuzzi, Carolina Natalia. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias; Argentina
Fil: Dedman, John. University of Cincinnati; Estados Unidos
Fil: Kaetzel, Marcia. University of Cincinnati; Estados Unidos
Fil: Wehrens, Xander H. T.. Baylor Coleege of Medicine. Cardiovascular Research Institute; Estados Unidos
Fil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
Fil: Palomeque, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares ; Argentina
description The impact of cardiac apoptosis in pre‐diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose‐rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca2+/calmodulin‐protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca2+ leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre‐diabetes. We generated a pre‐diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca2+ spontaneous events in the absence of SR Ca2+ load alterations vs. control‐diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [3H]ryanodine binding and CaMKII phosphorylation of RyR2‐S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia‐induced alterations. FRD also evoked cardiac apoptosis in WT mice vs. CD‐WT mice. Co‐treatment with the reactive oxygen species scavenger Tempol prevented FRD‐induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD‐SR‐AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR–mitochondrial distance vs. CD‐WT hearts. This remodelling was prevented in AC3I mice, with cardiac‐targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca2+ leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre‐diabetic heart. The FRD‐induced decrease in SR–mitochondrial distance is likely to additionally favour Ca2+ transit between the two organelles.
publishDate 2017
dc.date.none.fl_str_mv 2017-01-20
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/11336/49486
Federico, Marilén; Portiansky, Enrique Leo; Sommese, Leandro Matías; Alvarado, Francisco J.; Blanco, Paula Graciela; et al.; Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance; The Phisiological Society; The Journal Of Physiology; 595; 12; 20-1-2017; 4089-4108
0022-3751
1469-7793
CONICET Digital
CONICET
url http://hdl.handle.net/11336/49486
identifier_str_mv Federico, Marilén; Portiansky, Enrique Leo; Sommese, Leandro Matías; Alvarado, Francisco J.; Blanco, Paula Graciela; et al.; Calcium-calmodulin-dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance; The Phisiological Society; The Journal Of Physiology; 595; 12; 20-1-2017; 4089-4108
0022-3751
1469-7793
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP273714
info:eu-repo/semantics/altIdentifier/doi/10.1113/JP273714
info:eu-repo/semantics/altIdentifier/pmid/28105734
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471423/
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
application/pdf
dc.publisher.none.fl_str_mv The Phisiological Society
publisher.none.fl_str_mv The Phisiological Society
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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