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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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01519/full |
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| author | Zhenzhen Li Zhenzhen Li Zhenzhen Li Xiaoying Zhang Zhen Guo Zhen Guo Zhen Guo Yao Zhong Yao Zhong Yao Zhong Yao Zhong Panxia Wang Panxia Wang Panxia Wang Jingyan Li Jingyan Li Jingyan Li Zhuoming Li Zhuoming Li Zhuoming Li Peiqing Liu Peiqing Liu Peiqing Liu |
| author_facet | Zhenzhen Li Zhenzhen Li Zhenzhen Li Xiaoying Zhang Zhen Guo Zhen Guo Zhen Guo Yao Zhong Yao Zhong Yao Zhong Yao Zhong Panxia Wang Panxia Wang Panxia Wang Jingyan Li Jingyan Li Jingyan Li Zhuoming Li Zhuoming Li Zhuoming Li Peiqing Liu Peiqing Liu Peiqing Liu |
| author_sort | Zhenzhen Li |
| collection | DOAJ |
| 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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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T02:07:31Z |
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| spelling | doaj.art-3429605d2ae341a6b7ca1b36de1ec6862022-12-21T18:42:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-01-01910.3389/fphar.2018.01519415824SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte HypertrophyZhenzhen Li0Zhenzhen Li1Zhenzhen Li2Xiaoying Zhang3Zhen Guo4Zhen Guo5Zhen Guo6Yao Zhong7Yao Zhong8Yao Zhong9Yao Zhong10Panxia Wang11Panxia Wang12Panxia Wang13Jingyan Li14Jingyan Li15Jingyan Li16Zhuoming Li17Zhuoming Li18Zhuoming Li19Peiqing Liu20Peiqing Liu21Peiqing Liu22Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNational and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, School of Medicine, Xizang Minzu University, Shaanxi, ChinaDepartment of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNational and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNational and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Cardiology, Third People’s Hospital of Dongguan, Dongguan, ChinaDepartment of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNational and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNational and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNational and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNational and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaNFATc4, 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.https://www.frontiersin.org/article/10.3389/fphar.2018.01519/fullcardiomyocyte hypertrophySIRT6deacetylase activityNFATc4BNP |
| spellingShingle | Zhenzhen Li Zhenzhen Li Zhenzhen Li Xiaoying Zhang Zhen Guo Zhen Guo Zhen Guo Yao Zhong Yao Zhong Yao Zhong Yao Zhong Panxia Wang Panxia Wang Panxia Wang Jingyan Li Jingyan Li Jingyan Li Zhuoming Li Zhuoming Li Zhuoming Li Peiqing Liu Peiqing Liu Peiqing Liu SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy Frontiers in Pharmacology cardiomyocyte hypertrophy SIRT6 deacetylase activity NFATc4 BNP |
| 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 | cardiomyocyte hypertrophy SIRT6 deacetylase activity NFATc4 BNP |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.01519/full |
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