Cargando…

Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis

Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca(2+)-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na(+)](i) i...

Descripción completa

Detalles Bibliográficos
Autores principales: Morotti, Stefano, Ni, Haibo, Peters, Colin H., Rickert, Christian, Asgari-Targhi, Ameneh, Sato, Daisuke, Glukhov, Alexey V., Proenza, Catherine, Grandi, Eleonora
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198068/
https://www.ncbi.nlm.nih.gov/pubmed/34073281
http://dx.doi.org/10.3390/ijms22115645
_version_ 1783707049695117312
author Morotti, Stefano
Ni, Haibo
Peters, Colin H.
Rickert, Christian
Asgari-Targhi, Ameneh
Sato, Daisuke
Glukhov, Alexey V.
Proenza, Catherine
Grandi, Eleonora
author_facet Morotti, Stefano
Ni, Haibo
Peters, Colin H.
Rickert, Christian
Asgari-Targhi, Ameneh
Sato, Daisuke
Glukhov, Alexey V.
Proenza, Catherine
Grandi, Eleonora
author_sort Morotti, Stefano
collection PubMed
description Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca(2+)-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na(+)](i) is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na(+) homeostasis in SAN pacemaking and test whether [Na(+)](i) dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na(+) entry (Na(+)/Ca(2+) exchanger, NCX) and removal (Na(+)/K(+) ATPase, NKA). Results: We found that changes in intracellular Na(+) homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca(2+) and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na(+) homeostasis to Ca(2+) handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.
format Online
Article
Text
id pubmed-8198068
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-81980682021-06-14 Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis Morotti, Stefano Ni, Haibo Peters, Colin H. Rickert, Christian Asgari-Targhi, Ameneh Sato, Daisuke Glukhov, Alexey V. Proenza, Catherine Grandi, Eleonora Int J Mol Sci Article Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca(2+)-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na(+)](i) is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na(+) homeostasis in SAN pacemaking and test whether [Na(+)](i) dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na(+) entry (Na(+)/Ca(2+) exchanger, NCX) and removal (Na(+)/K(+) ATPase, NKA). Results: We found that changes in intracellular Na(+) homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca(2+) and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na(+) homeostasis to Ca(2+) handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function. MDPI 2021-05-26 /pmc/articles/PMC8198068/ /pubmed/34073281 http://dx.doi.org/10.3390/ijms22115645 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Morotti, Stefano
Ni, Haibo
Peters, Colin H.
Rickert, Christian
Asgari-Targhi, Ameneh
Sato, Daisuke
Glukhov, Alexey V.
Proenza, Catherine
Grandi, Eleonora
Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis
title Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis
title_full Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis
title_fullStr Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis
title_full_unstemmed Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis
title_short Intracellular Na(+) Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis
title_sort intracellular na(+) modulates pacemaking activity in murine sinoatrial node myocytes: an in silico analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198068/
https://www.ncbi.nlm.nih.gov/pubmed/34073281
http://dx.doi.org/10.3390/ijms22115645
work_keys_str_mv AT morottistefano intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT nihaibo intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT peterscolinh intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT rickertchristian intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT asgaritarghiameneh intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT satodaisuke intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT glukhovalexeyv intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT proenzacatherine intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis
AT grandieleonora intracellularnamodulatespacemakingactivityinmurinesinoatrialnodemyocytesaninsilicoanalysis