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A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice
Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca(2+) homeostasis, providing...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428569/ https://www.ncbi.nlm.nih.gov/pubmed/30896405 http://dx.doi.org/10.7554/eLife.41814 |
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author | Dai, Wenli Laforest, Brigitte Tyan, Leonid Shen, Kaitlyn M Nadadur, Rangarajan D Alvarado, Francisco J Mazurek, Stefan R Lazarevic, Sonja Gadek, Margaret Wang, Yitang Li, Ye Valdivia, Hector H Shen, Le Broman, Michael T Moskowitz, Ivan P Weber, Christopher R |
author_facet | Dai, Wenli Laforest, Brigitte Tyan, Leonid Shen, Kaitlyn M Nadadur, Rangarajan D Alvarado, Francisco J Mazurek, Stefan R Lazarevic, Sonja Gadek, Margaret Wang, Yitang Li, Ye Valdivia, Hector H Shen, Le Broman, Michael T Moskowitz, Ivan P Weber, Christopher R |
author_sort | Dai, Wenli |
collection | PubMed |
description | Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca(2+) homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca(2+) sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca(2+)-dependent pathway for AF risk. |
format | Online Article Text |
id | pubmed-6428569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-64285692019-03-25 A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice Dai, Wenli Laforest, Brigitte Tyan, Leonid Shen, Kaitlyn M Nadadur, Rangarajan D Alvarado, Francisco J Mazurek, Stefan R Lazarevic, Sonja Gadek, Margaret Wang, Yitang Li, Ye Valdivia, Hector H Shen, Le Broman, Michael T Moskowitz, Ivan P Weber, Christopher R eLife Human Biology and Medicine Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca(2+) homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca(2+) sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca(2+)-dependent pathway for AF risk. eLife Sciences Publications, Ltd 2019-03-21 /pmc/articles/PMC6428569/ /pubmed/30896405 http://dx.doi.org/10.7554/eLife.41814 Text en © 2019, Dai et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Human Biology and Medicine Dai, Wenli Laforest, Brigitte Tyan, Leonid Shen, Kaitlyn M Nadadur, Rangarajan D Alvarado, Francisco J Mazurek, Stefan R Lazarevic, Sonja Gadek, Margaret Wang, Yitang Li, Ye Valdivia, Hector H Shen, Le Broman, Michael T Moskowitz, Ivan P Weber, Christopher R A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice |
title | A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice |
title_full | A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice |
title_fullStr | A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice |
title_full_unstemmed | A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice |
title_short | A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice |
title_sort | calcium transport mechanism for atrial fibrillation in tbx5-mutant mice |
topic | Human Biology and Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428569/ https://www.ncbi.nlm.nih.gov/pubmed/30896405 http://dx.doi.org/10.7554/eLife.41814 |
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