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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...

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Autores principales: Shi, Yingchao, Fan, Wenli, Xu, Mingjie, Lin, Xinhua, Zhao, Wukui, Yang, Zhongzhou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
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.
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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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