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Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy
Ca(2+) is critical for cardiac electrical conduction and contractility, and aberrant Ca(2+) homeostasis causes arrhythmia and heart failure. Chromatin remodeling modulates gene expression involved in cardiac sarcomere assembly and postnatal heart function. However, the chromatin-remodeling regulator...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986070/ https://www.ncbi.nlm.nih.gov/pubmed/35167494 http://dx.doi.org/10.1172/jci.insight.148752 |
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author | Shi, Yingchao Fan, Wenli Xu, Mingjie Lin, Xinhua Zhao, Wukui Yang, Zhongzhou |
author_facet | Shi, Yingchao Fan, Wenli Xu, Mingjie Lin, Xinhua Zhao, Wukui Yang, Zhongzhou |
author_sort | Shi, Yingchao |
collection | PubMed |
description | Ca(2+) is critical for cardiac electrical conduction and contractility, and aberrant Ca(2+) homeostasis causes arrhythmia and heart failure. Chromatin remodeling modulates gene expression involved in cardiac sarcomere assembly and postnatal heart function. However, the chromatin-remodeling regulatory mechanism of cardiac Ca(2+) homeostasis is unknown. Here, we found that Znhit1, a core subunit of the SRCAP remodeling complex, was essential for heart function. Deletion of Znhit1 in postnatal hearts of mice resulted in arrhythmia, idiopathic vacuolar cardiomyopathy, rapid heart failure, and premature sudden death. In addition, the level of Casq1, a sarcoplasmic reticulum Ca(2+) regulatory protein, was massively elevated while SERCA2a showed reduced protein level. Mechanistically, the Znhit1 modulated the expression of Casq1 and SERCA2a by depositing H2A.Z at their promoters. Deletion of Casq1 could substantially alleviate the vacuolar formation in Znhit1 Casq1 KO mice. These findings demonstrate that Znhit1 is required for postnatal heart function and maintains cardiac Ca(2+) homeostasis and that accumulation of Casq1 might be a causative factor for vacuolar cardiomyopathy. |
format | Online Article Text |
id | pubmed-8986070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-89860702022-04-07 Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy Shi, Yingchao Fan, Wenli Xu, Mingjie Lin, Xinhua Zhao, Wukui Yang, Zhongzhou JCI Insight Research Article Ca(2+) is critical for cardiac electrical conduction and contractility, and aberrant Ca(2+) homeostasis causes arrhythmia and heart failure. Chromatin remodeling modulates gene expression involved in cardiac sarcomere assembly and postnatal heart function. However, the chromatin-remodeling regulatory mechanism of cardiac Ca(2+) homeostasis is unknown. Here, we found that Znhit1, a core subunit of the SRCAP remodeling complex, was essential for heart function. Deletion of Znhit1 in postnatal hearts of mice resulted in arrhythmia, idiopathic vacuolar cardiomyopathy, rapid heart failure, and premature sudden death. In addition, the level of Casq1, a sarcoplasmic reticulum Ca(2+) regulatory protein, was massively elevated while SERCA2a showed reduced protein level. Mechanistically, the Znhit1 modulated the expression of Casq1 and SERCA2a by depositing H2A.Z at their promoters. Deletion of Casq1 could substantially alleviate the vacuolar formation in Znhit1 Casq1 KO mice. These findings demonstrate that Znhit1 is required for postnatal heart function and maintains cardiac Ca(2+) homeostasis and that accumulation of Casq1 might be a causative factor for vacuolar cardiomyopathy. American Society for Clinical Investigation 2022-03-22 /pmc/articles/PMC8986070/ /pubmed/35167494 http://dx.doi.org/10.1172/jci.insight.148752 Text en © 2022 Shi et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Shi, Yingchao Fan, Wenli Xu, Mingjie Lin, Xinhua Zhao, Wukui Yang, Zhongzhou Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy |
title | Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy |
title_full | Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy |
title_fullStr | Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy |
title_full_unstemmed | Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy |
title_short | Critical role of Znhit1 for postnatal heart function and vacuolar cardiomyopathy |
title_sort | critical role of znhit1 for postnatal heart function and vacuolar cardiomyopathy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986070/ https://www.ncbi.nlm.nih.gov/pubmed/35167494 http://dx.doi.org/10.1172/jci.insight.148752 |
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