Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity

Autores
Fernandez Sada, E.; Silva Platas, C.; Villegas, C. A.; Rivero, S. L.; Willis, B. C.; García, N.; Garza, J. R.; Oropeza Almazán, Y.; Valverde, Carlos Alfredo; Mazzocchi, Gabriela; Zazueta, C.; Torre Amione, G.; García Rivas, G.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and Purpose: Despite the importance of mitochondrial Ca2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation. Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined. Key Results: The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling. Conclusions and Implications: Inhibition of the mitochondrial Ca2+ uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.
Fil: Fernandez Sada, E.. Tecnológico de Monterrey; México
Fil: Silva Platas, C.. Tecnológico de Monterrey; México
Fil: Villegas, C. A.. Tecnológico de Monterrey; México
Fil: Rivero, S. L.. Tecnológico de Monterrey; México
Fil: Willis, B. C.. Tecnológico de Monterrey; México
Fil: García, N.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; México
Fil: Garza, J. R.. Tecnológico de Monterrey; México
Fil: Oropeza Almazán, Y.. Tecnológico de Monterrey; México
Fil: Valverde, Carlos Alfredo. 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: Mazzocchi, Gabriela. 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: Zazueta, C.. Instituto Nacional de Cardiología ‘Ignacio Chávez’; México
Fil: Torre Amione, G.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; México
Fil: García Rivas, G.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; México
Materia
Mitochondria
Biochemical Pharmacology
Catecholamines
Ion Channles
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:11336/12024
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/12024
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activityFernandez Sada, E.Silva Platas, C.Villegas, C. A.Rivero, S. L.Willis, B. C.García, N.Garza, J. R.Oropeza Almazán, Y.Valverde, Carlos AlfredoMazzocchi, GabrielaZazueta, C.Torre Amione, G.García Rivas, G.MitochondriaBiochemical PharmacologyCatecholaminesIon Channleshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background and Purpose: Despite the importance of mitochondrial Ca2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation. Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined. Key Results: The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling. Conclusions and Implications: Inhibition of the mitochondrial Ca2+ uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.Fil: Fernandez Sada, E.. Tecnológico de Monterrey; MéxicoFil: Silva Platas, C.. Tecnológico de Monterrey; MéxicoFil: Villegas, C. A.. Tecnológico de Monterrey; MéxicoFil: Rivero, S. L.. Tecnológico de Monterrey; MéxicoFil: Willis, B. C.. Tecnológico de Monterrey; MéxicoFil: García, N.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; MéxicoFil: Garza, J. R.. Tecnológico de Monterrey; MéxicoFil: Oropeza Almazán, Y.. Tecnológico de Monterrey; MéxicoFil: Valverde, Carlos Alfredo. 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: Mazzocchi, Gabriela. 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: Zazueta, C.. Instituto Nacional de Cardiología ‘Ignacio Chávez’; MéxicoFil: Torre Amione, G.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; MéxicoFil: García Rivas, G.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; MéxicoWiley2014-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/12024Fernandez Sada, E.; Silva Platas, C.; Villegas, C. A.; Rivero, S. L.; Willis, B. C.; et al.; Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity; Wiley; British Journal Of Pharmacology; 171; 18; 9-2014; 4207-42210007-11881476-5381enginfo:eu-repo/semantics/altIdentifier/doi/10.1111/bph.12684info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/bph.12684/abstractinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:04:01Zoai:ri.conicet.gov.ar:11336/12024instacron: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:34982025-10-22 11:04:02.153CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
title Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
spellingShingle Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
Fernandez Sada, E.
Mitochondria
Biochemical Pharmacology
Catecholamines
Ion Channles
title_short Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
title_full Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
title_fullStr Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
title_full_unstemmed Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
title_sort Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
dc.creator.none.fl_str_mv Fernandez Sada, E.
Silva Platas, C.
Villegas, C. A.
Rivero, S. L.
Willis, B. C.
García, N.
Garza, J. R.
Oropeza Almazán, Y.
Valverde, Carlos Alfredo
Mazzocchi, Gabriela
Zazueta, C.
Torre Amione, G.
García Rivas, G.
author Fernandez Sada, E.
author_facet Fernandez Sada, E.
Silva Platas, C.
Villegas, C. A.
Rivero, S. L.
Willis, B. C.
García, N.
Garza, J. R.
Oropeza Almazán, Y.
Valverde, Carlos Alfredo
Mazzocchi, Gabriela
Zazueta, C.
Torre Amione, G.
García Rivas, G.
author_role author
author2 Silva Platas, C.
Villegas, C. A.
Rivero, S. L.
Willis, B. C.
García, N.
Garza, J. R.
Oropeza Almazán, Y.
Valverde, Carlos Alfredo
Mazzocchi, Gabriela
Zazueta, C.
Torre Amione, G.
García Rivas, G.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mitochondria
Biochemical Pharmacology
Catecholamines
Ion Channles
topic Mitochondria
Biochemical Pharmacology
Catecholamines
Ion Channles
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 and Purpose: Despite the importance of mitochondrial Ca2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation. Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined. Key Results: The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling. Conclusions and Implications: Inhibition of the mitochondrial Ca2+ uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.
Fil: Fernandez Sada, E.. Tecnológico de Monterrey; México
Fil: Silva Platas, C.. Tecnológico de Monterrey; México
Fil: Villegas, C. A.. Tecnológico de Monterrey; México
Fil: Rivero, S. L.. Tecnológico de Monterrey; México
Fil: Willis, B. C.. Tecnológico de Monterrey; México
Fil: García, N.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; México
Fil: Garza, J. R.. Tecnológico de Monterrey; México
Fil: Oropeza Almazán, Y.. Tecnológico de Monterrey; México
Fil: Valverde, Carlos Alfredo. 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: Mazzocchi, Gabriela. 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: Zazueta, C.. Instituto Nacional de Cardiología ‘Ignacio Chávez’; México
Fil: Torre Amione, G.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; México
Fil: García Rivas, G.. Tecnológico de Monterrey; México. Instituto de Cardiología y Medicina Vascular; México
description Background and Purpose: Despite the importance of mitochondrial Ca2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation. Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined. Key Results: The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling. Conclusions and Implications: Inhibition of the mitochondrial Ca2+ uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.
publishDate 2014
dc.date.none.fl_str_mv 2014-09
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/11336/12024
Fernandez Sada, E.; Silva Platas, C.; Villegas, C. A.; Rivero, S. L.; Willis, B. C.; et al.; Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity; Wiley; British Journal Of Pharmacology; 171; 18; 9-2014; 4207-4221
0007-1188
1476-5381
url http://hdl.handle.net/11336/12024
identifier_str_mv Fernandez Sada, E.; Silva Platas, C.; Villegas, C. A.; Rivero, S. L.; Willis, B. C.; et al.; Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity; Wiley; British Journal Of Pharmacology; 171; 18; 9-2014; 4207-4221
0007-1188
1476-5381
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1111/bph.12684
info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/bph.12684/abstract
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 Wiley
publisher.none.fl_str_mv Wiley
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 12.982451

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