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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/12024
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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 Técnicas2025-09-29T09:35:57Zoai: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:34982025-09-29 09:35:58.114CONICET 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) |
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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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1844613124652531712 |
score |
13.070432 |