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 journalArticle

2 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 languageEnglish (US)
Article numbere9127
JournalEMBO Molecular Medicine
Volume11
Issue number11
DOIs
StatePublished - Nov 7 2019

Keywords

  • MEF2a
  • cardiac hypertrophy
  • class IIa HDACs
  • nuclear receptor corepressor 1

ASJC Scopus subject areas

  • Molecular Medicine

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  • Cite this

    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), [e9127]. https://doi.org/10.15252/emmm.201809127