Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes

Ventricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological conditions, the complexity of calcium handling during...

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Autores: Conesa Ortega, David, Echebarría Domínguez, Blas, Peñaranda Ayllón, Angelina, Rodríguez Cantalapiedra, Inmaculada, Shiferaw, Yohannes, Álvarez Lacalle, Enrique
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Consejo General de la Arquitectura Técnica de España (CGATE)
Repositorio:RIARTE
OAI Identifier:oai:www.riarte.es:20.500.12251/2011
Acceso en línea:http://hdl.handle.net/20.500.12251/2011
https://doi.org/10.1371/journal.pcbi.1007572
Access Level:acceso abierto
Palabra clave:Corazón
Pared celular
Calcio
Homeostasis
Retículo sarcoplásmico (RS)
Terapia génica para insuficiencia cardíaca (SERCA)
Modelado BIM
Contracción ventricular
Medicina
2407.90 Estructura de la Pared Celular
2410.08 Histología Humana
2410.10 Fisiología Humana
2411.03 Fisiología Cardiovascular
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repository_id_str
spelling Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytesConesa Ortega, DavidEchebarría Domínguez, BlasPeñaranda Ayllón, AngelinaRodríguez Cantalapiedra, InmaculadaShiferaw, YohannesÁlvarez Lacalle, EnriqueCorazónPared celularCalcioHomeostasisRetículo sarcoplásmico (RS)Terapia génica para insuficiencia cardíaca (SERCA)Modelado BIMContracción ventricularMedicina2407.90 Estructura de la Pared Celular2410.08 Histología Humana2410.10 Fisiología Humana2411.03 Fisiología CardiovascularVentricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological conditions, the complexity of calcium handling during systole and diastole has made the prediction of its release at steady state impossible. Here we approach the problem analyzing the evolution of intracellular and extracellular calcium fluxes during a single beat which is away from homeostatic balance. Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the SR must fulfill simultaneously two different equalities. This renders calcium homeostasis as a problem that can be studied in terms of its equilibrium structure, leading to precise predictions of steady state from single-beat measurements. We show how changes in ion channels modify the general equilibrium, as shocks would do in general equilibrium macroeconomic models. This allows us to predict when an enhanced entrance of calcium in the cell reduces its contractibility and explain why SERCA gene therapy, a change in calcium handling to treat heart failure, might fail to improve contraction even when it successfully increases SERCA expression.Public Library of Science2020info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12251/2011https://doi.org/10.1371/journal.pcbi.1007572reponame:RIARTEinstname:Consejo General de la Arquitectura Técnica de España (CGATE)Ingléshttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:www.riarte.es:20.500.12251/20112026-06-02T12:44:41Z
dc.title.none.fl_str_mv Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
title Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
spellingShingle Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
Conesa Ortega, David
Corazón
Pared celular
Calcio
Homeostasis
Retículo sarcoplásmico (RS)
Terapia génica para insuficiencia cardíaca (SERCA)
Modelado BIM
Contracción ventricular
Medicina
2407.90 Estructura de la Pared Celular
2410.08 Histología Humana
2410.10 Fisiología Humana
2411.03 Fisiología Cardiovascular
title_short Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
title_full Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
title_fullStr Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
title_full_unstemmed Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
title_sort Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
dc.creator.none.fl_str_mv Conesa Ortega, David
Echebarría Domínguez, Blas
Peñaranda Ayllón, Angelina
Rodríguez Cantalapiedra, Inmaculada
Shiferaw, Yohannes
Álvarez Lacalle, Enrique
author Conesa Ortega, David
author_facet Conesa Ortega, David
Echebarría Domínguez, Blas
Peñaranda Ayllón, Angelina
Rodríguez Cantalapiedra, Inmaculada
Shiferaw, Yohannes
Álvarez Lacalle, Enrique
author_role author
author2 Echebarría Domínguez, Blas
Peñaranda Ayllón, Angelina
Rodríguez Cantalapiedra, Inmaculada
Shiferaw, Yohannes
Álvarez Lacalle, Enrique
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Corazón
Pared celular
Calcio
Homeostasis
Retículo sarcoplásmico (RS)
Terapia génica para insuficiencia cardíaca (SERCA)
Modelado BIM
Contracción ventricular
Medicina
2407.90 Estructura de la Pared Celular
2410.08 Histología Humana
2410.10 Fisiología Humana
2411.03 Fisiología Cardiovascular
topic Corazón
Pared celular
Calcio
Homeostasis
Retículo sarcoplásmico (RS)
Terapia génica para insuficiencia cardíaca (SERCA)
Modelado BIM
Contracción ventricular
Medicina
2407.90 Estructura de la Pared Celular
2410.08 Histología Humana
2410.10 Fisiología Humana
2411.03 Fisiología Cardiovascular
description Ventricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological conditions, the complexity of calcium handling during systole and diastole has made the prediction of its release at steady state impossible. Here we approach the problem analyzing the evolution of intracellular and extracellular calcium fluxes during a single beat which is away from homeostatic balance. Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the SR must fulfill simultaneously two different equalities. This renders calcium homeostasis as a problem that can be studied in terms of its equilibrium structure, leading to precise predictions of steady state from single-beat measurements. We show how changes in ion channels modify the general equilibrium, as shocks would do in general equilibrium macroeconomic models. This allows us to predict when an enhanced entrance of calcium in the cell reduces its contractibility and explain why SERCA gene therapy, a change in calcium handling to treat heart failure, might fail to improve contraction even when it successfully increases SERCA expression.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12251/2011
https://doi.org/10.1371/journal.pcbi.1007572
url http://hdl.handle.net/20.500.12251/2011
https://doi.org/10.1371/journal.pcbi.1007572
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:RIARTE
instname:Consejo General de la Arquitectura Técnica de España (CGATE)
instname_str Consejo General de la Arquitectura Técnica de España (CGATE)
reponame_str RIARTE
collection RIARTE
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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