Cargando…
Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy
The heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca(2+) dynamics. Little is known about the physiological processes preceding i...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660846/ https://www.ncbi.nlm.nih.gov/pubmed/34887420 http://dx.doi.org/10.1038/s41467-021-27461-8 |
_version_ | 1784613278031282176 |
---|---|
author | Kamel, S. M. van Opbergen, C. J. M. Koopman, C. D. Verkerk, A. O. Boukens, B. J. D. de Jonge, B. Onderwater, Y. L. van Alebeek, E. Chocron, S. Polidoro Pontalti, C. Weuring, W. J. Vos, M. A. de Boer, T. P. van Veen, T. A. B. Bakkers, J. |
author_facet | Kamel, S. M. van Opbergen, C. J. M. Koopman, C. D. Verkerk, A. O. Boukens, B. J. D. de Jonge, B. Onderwater, Y. L. van Alebeek, E. Chocron, S. Polidoro Pontalti, C. Weuring, W. J. Vos, M. A. de Boer, T. P. van Veen, T. A. B. Bakkers, J. |
author_sort | Kamel, S. M. |
collection | PubMed |
description | The heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca(2+) dynamics. Little is known about the physiological processes preceding induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we address these issues using a knock-in Phospholamban p.Arg14del zebrafish model. Hearts from adult zebrafish with this mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography reveals contractile variations before overt structural changes occur, which correlates at the cellular level with action potential duration alternans. These functional alterations are preceded by diminished Ca(2+) transient amplitudes in embryonic hearts as well as an increase in diastolic Ca(2+) level, slower Ca(2+) transient decay and longer Ca(2+) transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca(2+) dysregulation, rescues the cellular action potential duration alternans, while it improves cardiac relaxation. Thus, we present insight into the pathophysiology of Phospholamban p.Arg14del cardiomyopathy. |
format | Online Article Text |
id | pubmed-8660846 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86608462021-12-27 Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy Kamel, S. M. van Opbergen, C. J. M. Koopman, C. D. Verkerk, A. O. Boukens, B. J. D. de Jonge, B. Onderwater, Y. L. van Alebeek, E. Chocron, S. Polidoro Pontalti, C. Weuring, W. J. Vos, M. A. de Boer, T. P. van Veen, T. A. B. Bakkers, J. Nat Commun Article The heterozygous Phospholamban p.Arg14del mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. This mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca(2+) dynamics. Little is known about the physiological processes preceding induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we address these issues using a knock-in Phospholamban p.Arg14del zebrafish model. Hearts from adult zebrafish with this mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography reveals contractile variations before overt structural changes occur, which correlates at the cellular level with action potential duration alternans. These functional alterations are preceded by diminished Ca(2+) transient amplitudes in embryonic hearts as well as an increase in diastolic Ca(2+) level, slower Ca(2+) transient decay and longer Ca(2+) transients in cells of adult hearts. We find that istaroxime treatment ameliorates the in vivo Ca(2+) dysregulation, rescues the cellular action potential duration alternans, while it improves cardiac relaxation. Thus, we present insight into the pathophysiology of Phospholamban p.Arg14del cardiomyopathy. Nature Publishing Group UK 2021-12-09 /pmc/articles/PMC8660846/ /pubmed/34887420 http://dx.doi.org/10.1038/s41467-021-27461-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kamel, S. M. van Opbergen, C. J. M. Koopman, C. D. Verkerk, A. O. Boukens, B. J. D. de Jonge, B. Onderwater, Y. L. van Alebeek, E. Chocron, S. Polidoro Pontalti, C. Weuring, W. J. Vos, M. A. de Boer, T. P. van Veen, T. A. B. Bakkers, J. Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy |
title | Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy |
title_full | Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy |
title_fullStr | Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy |
title_full_unstemmed | Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy |
title_short | Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy |
title_sort | istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban r14del cardiomyopathy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660846/ https://www.ncbi.nlm.nih.gov/pubmed/34887420 http://dx.doi.org/10.1038/s41467-021-27461-8 |
work_keys_str_mv | AT kamelsm istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT vanopbergencjm istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT koopmancd istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT verkerkao istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT boukensbjd istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT dejongeb istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT onderwateryl istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT vanalebeeke istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT chocrons istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT polidoropontaltic istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT weuringwj istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT vosma istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT deboertp istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT vanveentab istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy AT bakkersj istaroximetreatmentamelioratescalciumdysregulationinazebrafishmodelofphospholambanr14delcardiomyopathy |