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SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy

NFATc4, a member from the Nuclear Factor of Activated T cells (NFATs) transcription factor family, plays a pivotal role in the development of cardiac hypertrophy. NFATc4 is dephosphorylated by calcineurin and translocated from the cytoplasm to the nucleus to regulate the expression of hypertrophic g...

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Autores principales: Li, Zhenzhen, Zhang, Xiaoying, Guo, Zhen, Zhong, Yao, Wang, Panxia, Li, Jingyan, Li, Zhuoming, Liu, Peiqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331469/
https://www.ncbi.nlm.nih.gov/pubmed/30670969
http://dx.doi.org/10.3389/fphar.2018.01519
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author Li, Zhenzhen
Zhang, Xiaoying
Guo, Zhen
Zhong, Yao
Wang, Panxia
Li, Jingyan
Li, Zhuoming
Liu, Peiqing
author_facet Li, Zhenzhen
Zhang, Xiaoying
Guo, Zhen
Zhong, Yao
Wang, Panxia
Li, Jingyan
Li, Zhuoming
Liu, Peiqing
author_sort Li, Zhenzhen
collection PubMed
description NFATc4, a member from the Nuclear Factor of Activated T cells (NFATs) transcription factor family, plays a pivotal role in the development of cardiac hypertrophy. NFATc4 is dephosphorylated by calcineurin and translocated from the cytoplasm to the nucleus to regulate the expression of hypertrophic genes, like brain natriuretic polypeptide (BNP). The present study identified SIRT6, an important subtype of NAD(+) dependent class III histone deacetylase, to be a negative regulator of NFATc4 in cardiomyocyte hypertrophy. In phenylephrine (PE)-induced hypertrophic cardiomyocyte model, overexpression of SIRT6 by adenovirus infection or by plasmid transfection repressed the protein and mRNA expressions of NFATc4, elevated its phosphorylation level, prevented its nuclear accumulation, subsequently suppressed its transcriptional activity and downregulated its target gene BNP. By contrast, mutant of SIRT6 without deacetylase activity (H133Y) did not demonstrate these effects, suggesting that the inhibitory effect of SIRT6 on NFATc4 was dependent on its deacetylase activity. Moreover, the effect of SIRT6 overexpression on repressing BNP expression was reversed by NFATc4 replenishment, whereas the effect of SIRT6 deficiency on upregulating BNP was recovered by NFATc4 silencing. Mechanistically, interactions between SIRT6 and NFATc4 might possibly facilitate the deacetylation of NFATc4 by SIRT6, thereby preventing the activation of NFATc4. In conclusion, the present study reveals that SIRT6 suppresses the expression and activation of NFATc4. These findings provide more evidences of the anti-hypertrophic effect of SIRT6 and suggest SIRT6 as a potential therapeutic target for cardiac hypertrophy.
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spelling pubmed-63314692019-01-22 SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy Li, Zhenzhen Zhang, Xiaoying Guo, Zhen Zhong, Yao Wang, Panxia Li, Jingyan Li, Zhuoming Liu, Peiqing Front Pharmacol Pharmacology NFATc4, a member from the Nuclear Factor of Activated T cells (NFATs) transcription factor family, plays a pivotal role in the development of cardiac hypertrophy. NFATc4 is dephosphorylated by calcineurin and translocated from the cytoplasm to the nucleus to regulate the expression of hypertrophic genes, like brain natriuretic polypeptide (BNP). The present study identified SIRT6, an important subtype of NAD(+) dependent class III histone deacetylase, to be a negative regulator of NFATc4 in cardiomyocyte hypertrophy. In phenylephrine (PE)-induced hypertrophic cardiomyocyte model, overexpression of SIRT6 by adenovirus infection or by plasmid transfection repressed the protein and mRNA expressions of NFATc4, elevated its phosphorylation level, prevented its nuclear accumulation, subsequently suppressed its transcriptional activity and downregulated its target gene BNP. By contrast, mutant of SIRT6 without deacetylase activity (H133Y) did not demonstrate these effects, suggesting that the inhibitory effect of SIRT6 on NFATc4 was dependent on its deacetylase activity. Moreover, the effect of SIRT6 overexpression on repressing BNP expression was reversed by NFATc4 replenishment, whereas the effect of SIRT6 deficiency on upregulating BNP was recovered by NFATc4 silencing. Mechanistically, interactions between SIRT6 and NFATc4 might possibly facilitate the deacetylation of NFATc4 by SIRT6, thereby preventing the activation of NFATc4. In conclusion, the present study reveals that SIRT6 suppresses the expression and activation of NFATc4. These findings provide more evidences of the anti-hypertrophic effect of SIRT6 and suggest SIRT6 as a potential therapeutic target for cardiac hypertrophy. Frontiers Media S.A. 2019-01-08 /pmc/articles/PMC6331469/ /pubmed/30670969 http://dx.doi.org/10.3389/fphar.2018.01519 Text en Copyright © 2019 Li, Zhang, Guo, Zhong, Wang, Li, Li and Liu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Li, Zhenzhen
Zhang, Xiaoying
Guo, Zhen
Zhong, Yao
Wang, Panxia
Li, Jingyan
Li, Zhuoming
Liu, Peiqing
SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
title SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
title_full SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
title_fullStr SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
title_full_unstemmed SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
title_short SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy
title_sort sirt6 suppresses nfatc4 expression and activation in cardiomyocyte hypertrophy
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331469/
https://www.ncbi.nlm.nih.gov/pubmed/30670969
http://dx.doi.org/10.3389/fphar.2018.01519
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