Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells
Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility t...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199257/ https://www.ncbi.nlm.nih.gov/pubmed/30353147 http://dx.doi.org/10.1038/s41598-018-33958-y |
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author | Bai, Jieyun Gladding, Patrick A. Stiles, Martin K. Fedorov, Vadim V. Zhao, Jichao |
author_facet | Bai, Jieyun Gladding, Patrick A. Stiles, Martin K. Fedorov, Vadim V. Zhao, Jichao |
author_sort | Bai, Jieyun |
collection | PubMed |
description | Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility to AF in patients with TBX5/PITX2 insufficiency remain unclear. In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF. Using our TPA model, we have demonstrated that spontaneous diastolic depolarization observed in atrial myocytes with TBX5-deletion can be explained by altered intracellular calcium handling and suppression of inward-rectifier potassium current (I(K1)). Additionally, our computer simulation results shed new light on the novel cellular mechanism underlying AF by indicating that the imbalance between suppressed outward current I(K1) and increased inward sodium-calcium exchanger current (I(NCX)) resulted from SR calcium leak leads to spontaneous depolarizations. Furthermore, our simulation results suggest that these arrhythmogenic triggers can be potentially suppressed by inhibiting sarcoplasmic reticulum (SR) calcium leak and reversing remodeled I(K1). More importantly, this study has clinically significant implications on the drugs used for maintaining SR calcium homeostasis, whereby drugs such as dantrolene may confer significant improvement for the treatment of AF patients with TBX5/PITX2 insufficiency. |
format | Online Article Text |
id | pubmed-6199257 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61992572018-10-25 Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells Bai, Jieyun Gladding, Patrick A. Stiles, Martin K. Fedorov, Vadim V. Zhao, Jichao Sci Rep Article Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility to AF in patients with TBX5/PITX2 insufficiency remain unclear. In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF. Using our TPA model, we have demonstrated that spontaneous diastolic depolarization observed in atrial myocytes with TBX5-deletion can be explained by altered intracellular calcium handling and suppression of inward-rectifier potassium current (I(K1)). Additionally, our computer simulation results shed new light on the novel cellular mechanism underlying AF by indicating that the imbalance between suppressed outward current I(K1) and increased inward sodium-calcium exchanger current (I(NCX)) resulted from SR calcium leak leads to spontaneous depolarizations. Furthermore, our simulation results suggest that these arrhythmogenic triggers can be potentially suppressed by inhibiting sarcoplasmic reticulum (SR) calcium leak and reversing remodeled I(K1). More importantly, this study has clinically significant implications on the drugs used for maintaining SR calcium homeostasis, whereby drugs such as dantrolene may confer significant improvement for the treatment of AF patients with TBX5/PITX2 insufficiency. Nature Publishing Group UK 2018-10-23 /pmc/articles/PMC6199257/ /pubmed/30353147 http://dx.doi.org/10.1038/s41598-018-33958-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Bai, Jieyun Gladding, Patrick A. Stiles, Martin K. Fedorov, Vadim V. Zhao, Jichao Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells |
title | Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells |
title_full | Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells |
title_fullStr | Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells |
title_full_unstemmed | Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells |
title_short | Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells |
title_sort | ionic and cellular mechanisms underlying tbx5/pitx2 insufficiency-induced atrial fibrillation: insights from mathematical models of human atrial cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199257/ https://www.ncbi.nlm.nih.gov/pubmed/30353147 http://dx.doi.org/10.1038/s41598-018-33958-y |
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