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.

中文翻译：

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核受体corepressor 1抑制心脏肥大。

尚不清楚心肌细胞中核受体共抑制因子1（NCoR1）的功能，其生理和病理意义尚不清楚。在这里，我们发现心肌细胞特异性NCoR1基因敲除（CMNKO）小鼠在基线时表现出心脏肥大，并且在压力超负荷后具有更严重的心脏肥大和功能障碍。NCoR1的敲低加剧，而过表达减轻了去氧肾上腺素引起的心肌肥大。机理研究表明，肌细胞增强因子2a（MEF2a）和MEF2d介导了NCoR1对心肌肥大的影响。NCoR1的受体相互作用域（RID）与MEF2a相互作用以抑制其转录活性。此外，NCoR1与MEF2a和IIa类组蛋白脱乙酰基酶（HDAC）形成复合物，以抑制肥大相关基因。最后，心脏中NCoR1的RID的过表达减轻了压力超负荷引起的心脏肥大和功能障碍。总之，NCoR1与MEF2和HDAC共同抑制心脏肥大。靶向NCoR1和MEF2 / HDACs复合物可能是解决病理性心脏肥大的一种有吸引力的治疗策略。