Nuclear receptor corepressor 1 represses cardiac hypertrophy

Chao Li; Xue Nan Sun; Bo Yan Chen; Meng Ru Zeng; Lin Juan Du; Ting Liu; Hui Hui Gu; Yuan Liu; Yu Lin Li; Lu Jun Zhou; Xiao Jun Zheng; Yu Yao Zhang; Wu Chang Zhang; Yan Liu; Chaoji Shi; Shuai Shao; Xue Rui Shi; Yi Yi; Xu Liu; Jun Wang; Johan Auwerx; Zhao V. Wang; Feng Jia; Ruo Gu Li; Sheng Zhong Duan

doi:10.15252/emmm.201809127

Nuclear receptor corepressor 1 represses cardiac hypertrophy

Chao Li, Xue Nan Sun, Bo Yan Chen, Meng Ru Zeng, Lin Juan Du, Ting Liu, Hui Hui Gu, Yuan Liu, Yu Lin Li, Lu Jun Zhou, Xiao Jun Zheng, Yu Yao Zhang, Wu Chang Zhang, Yan Liu, Chaoji Shi, Shuai Shao, Xue Rui Shi, Yi Yi, Xu Liu, Jun WangJohan Auwerx, Zhao V. Wang, Feng Jia, Ruo Gu Li, Sheng Zhong Duan

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.

Original language	English (US)
Article number	e9127
Journal	EMBO Molecular Medicine
Volume	11
Issue number	11
DOIs	https://doi.org/10.15252/emmm.201809127
State	Published - Nov 7 2019

Keywords

MEF2a
cardiac hypertrophy
class IIa HDACs
nuclear receptor corepressor 1

ASJC Scopus subject areas

Molecular Medicine

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10.15252/emmm.201809127

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Li, C., Sun, X. N., Chen, B. Y., Zeng, M. R., Du, L. J., Liu, T., Gu, H. H., Liu, Y., Li, Y. L., Zhou, L. J., Zheng, X. J., Zhang, Y. Y., Zhang, W. C., Liu, Y., Shi, C., Shao, S., Shi, X. R., Yi, Y., Liu, X., ... Duan, S. Z. (2019). Nuclear receptor corepressor 1 represses cardiac hypertrophy. EMBO Molecular Medicine, 11(11), Article e9127. https://doi.org/10.15252/emmm.201809127

Li, C, Sun, XN, Chen, BY, Zeng, MR, Du, LJ, Liu, T, Gu, HH, Liu, Y, Li, YL, Zhou, LJ, Zheng, XJ, Zhang, YY, Zhang, WC, Liu, Y, Shi, C, Shao, S, Shi, XR, Yi, Y, Liu, X, Wang, J, Auwerx, J, Wang, ZV, Jia, F, Li, RG & Duan, SZ 2019, 'Nuclear receptor corepressor 1 represses cardiac hypertrophy', EMBO Molecular Medicine, vol. 11, no. 11, e9127. https://doi.org/10.15252/emmm.201809127

@article{297411d7a892456fa42011124aaf780b,

title = "Nuclear receptor corepressor 1 represses cardiac hypertrophy",

abstract = "The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.",

keywords = "MEF2a, cardiac hypertrophy, class IIa HDACs, nuclear receptor corepressor 1",

author = "Chao Li and Sun, {Xue Nan} and Chen, {Bo Yan} and Zeng, {Meng Ru} and Du, {Lin Juan} and Ting Liu and Gu, {Hui Hui} and Yuan Liu and Li, {Yu Lin} and Zhou, {Lu Jun} and Zheng, {Xiao Jun} and Zhang, {Yu Yao} and Zhang, {Wu Chang} and Yan Liu and Chaoji Shi and Shuai Shao and Shi, {Xue Rui} and Yi Yi and Xu Liu and Jun Wang and Johan Auwerx and Wang, {Zhao V.} and Feng Jia and Li, {Ruo Gu} and Duan, {Sheng Zhong}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2019",

month = nov,

day = "7",

doi = "10.15252/emmm.201809127",

language = "English (US)",

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AU - Sun, Xue Nan

AU - Chen, Bo Yan

AU - Zeng, Meng Ru

AU - Du, Lin Juan

AU - Liu, Ting

AU - Gu, Hui Hui

AU - Liu, Yuan

AU - Li, Yu Lin

AU - Zhou, Lu Jun

AU - Zheng, Xiao Jun

AU - Zhang, Yu Yao

AU - Zhang, Wu Chang

AU - Liu, Yan

AU - Shi, Chaoji

AU - Shao, Shuai

AU - Shi, Xue Rui

AU - Yi, Yi

AU - Liu, Xu

AU - Wang, Jun

AU - Auwerx, Johan

AU - Wang, Zhao V.

AU - Jia, Feng

AU - Li, Ruo Gu

AU - Duan, Sheng Zhong

PY - 2019/11/7

Y1 - 2019/11/7

N2 - The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.

AB - The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.

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ER -

Nuclear receptor corepressor 1 represses cardiac hypertrophy

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Keywords

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