Role of CaMKII and ROS in rapid pacing-induced apoptosis

Autores
Sepúlveda, Marisa Noemí; Gonano, Luis Alberto; Back, Tom G.; Chen, S. R. Wayne; Vila Petroff, Martin Gerarde
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tachycardia promotes cell death and cardiac remodeling, leading to congestive heart failure. However, the underlying mechanism of tachycardia- or rapid pacing (RP)-induced cell death remains unknown. Myocyte loss by apoptosis is recognized as a critical factor in the progression to heart failure and simulation of tachycardia by RP has been shown to increase the intracellular levels of at least two potentially proapoptotic molecules, Ca2 + and reactive oxygen species (ROS). However, whether these molecules mediate tachycardia- or RP-induced cell death has yet to be determined. The aim of this study was to examine the subcellular mechanisms underlying RP-induced apoptosis. For this purpose rat ventricular myocytes were maintained quiescent or paced at 0.5, 5 and 8 Hz for 1 hr. RP at 5 and 8 Hz decreased myocyte viability by 58 ± 3% and 75 ± 6% (n = 24), respectively, compared to cells maintained at 0.5 Hz, and increased caspase-3 activity and Bax/Bcl-2 ratio, indicative of apoptosis. RP-induced cell death and apoptosis were prevented when pacing protocols were conducted in the presence of either the ROS scavenger, MPG, or nifedipine to reduce Ca2 + entry or the CaMKII inhibitors, KN93 and AIP. Consistently, myocytes from transgenic mice expressing a CaMKII inhibitory peptide (AC3-I) were protected against RP-induced cell death. Interestingly, tetracaine and carvedilol used to reduce ryanodine receptor (RyR) diastolic Ca2 + release, and ruthenium red used to prevent Ca2 + entry into the mitochondria prevented RP-induced cell death, whereas PI3K inhibition with Wortmannin exacerbated pacing-induced cell mortality. We conclude that CaMKII activation and ROS production are involved in RP-induced apoptosis. Particularly, our results suggest that CaMKII-dependent posttranslational modifications of the cardiac ryanodine receptor (RyR) leading to enhanced diastolic Ca2 + release and mitochondrial Ca2 + overload could be the underlying mechanism involved. We further show that RP simultaneously activates a protective cascade involving PI3K/AKT signaling which is however, insufficient to completely suppress apoptosis.
Fil: Sepúlveda, Marisa Noemí. 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: Gonano, Luis Alberto. 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: Back, Tom G.. University Of Calgary; Canadá
Fil: Chen, S. R. Wayne. University Of Calgary; Canadá
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
Materia
Tachycardia
Apoptosis
Calcium
Ros
Camkii
Heart Failure
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/11944
Acceder
id CONICETDig_dd3bf8d0a0efa7a7ca40728b61f8f7a8
oai_identifier_str oai:ri.conicet.gov.ar:11336/11944
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Role of CaMKII and ROS in rapid pacing-induced apoptosisSepúlveda, Marisa NoemíGonano, Luis AlbertoBack, Tom G.Chen, S. R. WayneVila Petroff, Martin GerardeTachycardiaApoptosisCalciumRosCamkiiHeart Failurehttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Tachycardia promotes cell death and cardiac remodeling, leading to congestive heart failure. However, the underlying mechanism of tachycardia- or rapid pacing (RP)-induced cell death remains unknown. Myocyte loss by apoptosis is recognized as a critical factor in the progression to heart failure and simulation of tachycardia by RP has been shown to increase the intracellular levels of at least two potentially proapoptotic molecules, Ca2 + and reactive oxygen species (ROS). However, whether these molecules mediate tachycardia- or RP-induced cell death has yet to be determined. The aim of this study was to examine the subcellular mechanisms underlying RP-induced apoptosis. For this purpose rat ventricular myocytes were maintained quiescent or paced at 0.5, 5 and 8 Hz for 1 hr. RP at 5 and 8 Hz decreased myocyte viability by 58 ± 3% and 75 ± 6% (n = 24), respectively, compared to cells maintained at 0.5 Hz, and increased caspase-3 activity and Bax/Bcl-2 ratio, indicative of apoptosis. RP-induced cell death and apoptosis were prevented when pacing protocols were conducted in the presence of either the ROS scavenger, MPG, or nifedipine to reduce Ca2 + entry or the CaMKII inhibitors, KN93 and AIP. Consistently, myocytes from transgenic mice expressing a CaMKII inhibitory peptide (AC3-I) were protected against RP-induced cell death. Interestingly, tetracaine and carvedilol used to reduce ryanodine receptor (RyR) diastolic Ca2 + release, and ruthenium red used to prevent Ca2 + entry into the mitochondria prevented RP-induced cell death, whereas PI3K inhibition with Wortmannin exacerbated pacing-induced cell mortality. We conclude that CaMKII activation and ROS production are involved in RP-induced apoptosis. Particularly, our results suggest that CaMKII-dependent posttranslational modifications of the cardiac ryanodine receptor (RyR) leading to enhanced diastolic Ca2 + release and mitochondrial Ca2 + overload could be the underlying mechanism involved. We further show that RP simultaneously activates a protective cascade involving PI3K/AKT signaling which is however, insufficient to completely suppress apoptosis.Fil: Sepúlveda, Marisa Noemí. 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: Gonano, Luis Alberto. 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: Back, Tom G.. University Of Calgary; CanadáFil: Chen, S. R. Wayne. University Of Calgary; CanadáFil: 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; ArgentinaElsevier2013-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/11944Sepúlveda, Marisa Noemí; Gonano, Luis Alberto; Back, Tom G.; Chen, S. R. Wayne; Vila Petroff, Martin Gerarde; Role of CaMKII and ROS in rapid pacing-induced apoptosis; Elsevier; Journal Of Molecular And Cellular Cardiology; 63; 10-2013; 135-1450022-2828enginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.yjmcc.2013.07.013info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0022282813002460info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-29T12:03:21Zoai:ri.conicet.gov.ar:11336/11944instacron: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:34982025-10-29 12:03:21.568CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Role of CaMKII and ROS in rapid pacing-induced apoptosis
title Role of CaMKII and ROS in rapid pacing-induced apoptosis
spellingShingle Role of CaMKII and ROS in rapid pacing-induced apoptosis
Sepúlveda, Marisa Noemí
Tachycardia
Apoptosis
Calcium
Ros
Camkii
Heart Failure
title_short Role of CaMKII and ROS in rapid pacing-induced apoptosis
title_full Role of CaMKII and ROS in rapid pacing-induced apoptosis
title_fullStr Role of CaMKII and ROS in rapid pacing-induced apoptosis
title_full_unstemmed Role of CaMKII and ROS in rapid pacing-induced apoptosis
title_sort Role of CaMKII and ROS in rapid pacing-induced apoptosis
dc.creator.none.fl_str_mv Sepúlveda, Marisa Noemí
Gonano, Luis Alberto
Back, Tom G.
Chen, S. R. Wayne
Vila Petroff, Martin Gerarde
author Sepúlveda, Marisa Noemí
author_facet Sepúlveda, Marisa Noemí
Gonano, Luis Alberto
Back, Tom G.
Chen, S. R. Wayne
Vila Petroff, Martin Gerarde
author_role author
author2 Gonano, Luis Alberto
Back, Tom G.
Chen, S. R. Wayne
Vila Petroff, Martin Gerarde
author2_role author
author
author
author
dc.subject.none.fl_str_mv Tachycardia
Apoptosis
Calcium
Ros
Camkii
Heart Failure
topic Tachycardia
Apoptosis
Calcium
Ros
Camkii
Heart Failure
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Tachycardia promotes cell death and cardiac remodeling, leading to congestive heart failure. However, the underlying mechanism of tachycardia- or rapid pacing (RP)-induced cell death remains unknown. Myocyte loss by apoptosis is recognized as a critical factor in the progression to heart failure and simulation of tachycardia by RP has been shown to increase the intracellular levels of at least two potentially proapoptotic molecules, Ca2 + and reactive oxygen species (ROS). However, whether these molecules mediate tachycardia- or RP-induced cell death has yet to be determined. The aim of this study was to examine the subcellular mechanisms underlying RP-induced apoptosis. For this purpose rat ventricular myocytes were maintained quiescent or paced at 0.5, 5 and 8 Hz for 1 hr. RP at 5 and 8 Hz decreased myocyte viability by 58 ± 3% and 75 ± 6% (n = 24), respectively, compared to cells maintained at 0.5 Hz, and increased caspase-3 activity and Bax/Bcl-2 ratio, indicative of apoptosis. RP-induced cell death and apoptosis were prevented when pacing protocols were conducted in the presence of either the ROS scavenger, MPG, or nifedipine to reduce Ca2 + entry or the CaMKII inhibitors, KN93 and AIP. Consistently, myocytes from transgenic mice expressing a CaMKII inhibitory peptide (AC3-I) were protected against RP-induced cell death. Interestingly, tetracaine and carvedilol used to reduce ryanodine receptor (RyR) diastolic Ca2 + release, and ruthenium red used to prevent Ca2 + entry into the mitochondria prevented RP-induced cell death, whereas PI3K inhibition with Wortmannin exacerbated pacing-induced cell mortality. We conclude that CaMKII activation and ROS production are involved in RP-induced apoptosis. Particularly, our results suggest that CaMKII-dependent posttranslational modifications of the cardiac ryanodine receptor (RyR) leading to enhanced diastolic Ca2 + release and mitochondrial Ca2 + overload could be the underlying mechanism involved. We further show that RP simultaneously activates a protective cascade involving PI3K/AKT signaling which is however, insufficient to completely suppress apoptosis.
Fil: Sepúlveda, Marisa Noemí. 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: Gonano, Luis Alberto. 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: Back, Tom G.. University Of Calgary; Canadá
Fil: Chen, S. R. Wayne. University Of Calgary; Canadá
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
description Tachycardia promotes cell death and cardiac remodeling, leading to congestive heart failure. However, the underlying mechanism of tachycardia- or rapid pacing (RP)-induced cell death remains unknown. Myocyte loss by apoptosis is recognized as a critical factor in the progression to heart failure and simulation of tachycardia by RP has been shown to increase the intracellular levels of at least two potentially proapoptotic molecules, Ca2 + and reactive oxygen species (ROS). However, whether these molecules mediate tachycardia- or RP-induced cell death has yet to be determined. The aim of this study was to examine the subcellular mechanisms underlying RP-induced apoptosis. For this purpose rat ventricular myocytes were maintained quiescent or paced at 0.5, 5 and 8 Hz for 1 hr. RP at 5 and 8 Hz decreased myocyte viability by 58 ± 3% and 75 ± 6% (n = 24), respectively, compared to cells maintained at 0.5 Hz, and increased caspase-3 activity and Bax/Bcl-2 ratio, indicative of apoptosis. RP-induced cell death and apoptosis were prevented when pacing protocols were conducted in the presence of either the ROS scavenger, MPG, or nifedipine to reduce Ca2 + entry or the CaMKII inhibitors, KN93 and AIP. Consistently, myocytes from transgenic mice expressing a CaMKII inhibitory peptide (AC3-I) were protected against RP-induced cell death. Interestingly, tetracaine and carvedilol used to reduce ryanodine receptor (RyR) diastolic Ca2 + release, and ruthenium red used to prevent Ca2 + entry into the mitochondria prevented RP-induced cell death, whereas PI3K inhibition with Wortmannin exacerbated pacing-induced cell mortality. We conclude that CaMKII activation and ROS production are involved in RP-induced apoptosis. Particularly, our results suggest that CaMKII-dependent posttranslational modifications of the cardiac ryanodine receptor (RyR) leading to enhanced diastolic Ca2 + release and mitochondrial Ca2 + overload could be the underlying mechanism involved. We further show that RP simultaneously activates a protective cascade involving PI3K/AKT signaling which is however, insufficient to completely suppress apoptosis.
publishDate 2013
dc.date.none.fl_str_mv 2013-10
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/11336/11944
Sepúlveda, Marisa Noemí; Gonano, Luis Alberto; Back, Tom G.; Chen, S. R. Wayne; Vila Petroff, Martin Gerarde; Role of CaMKII and ROS in rapid pacing-induced apoptosis; Elsevier; Journal Of Molecular And Cellular Cardiology; 63; 10-2013; 135-145
0022-2828
url http://hdl.handle.net/11336/11944
identifier_str_mv Sepúlveda, Marisa Noemí; Gonano, Luis Alberto; Back, Tom G.; Chen, S. R. Wayne; Vila Petroff, Martin Gerarde; Role of CaMKII and ROS in rapid pacing-induced apoptosis; Elsevier; Journal Of Molecular And Cellular Cardiology; 63; 10-2013; 135-145
0022-2828
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.yjmcc.2013.07.013
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0022282813002460
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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
_version_ 1847426805052473344
score 13.10058

Publicaciones similares