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Nature Communications Pub Date : 2025-01-02 DOI:10.1038/s41467-024-55557-4

Peilu She, Bangjun Gao, Dongliang Li, Chen Wu, Xuejiao Zhu, Yuan He, Fei Mo, Yao Qi, Daqing Jin, Yewei Chen, Xin Zhao, Jinzhong Lin, Hairong Hu, Jia Li, Bing Zhang, Peng Xie, Chengqi Lin, Vincent M Christoffels, Yueheng Wu, Ping Zhu, Tao P Zhong

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引用次数: 0

摘要

心肌细胞的能量剥夺和代谢重构是公认的心力衰竭特征。在这里，我们报告了 HEY2（一种与毛发/增殖分裂相关的转录抑制因子）在扩张型心肌病患者的心脏中上调。诱导 HEY2 在斑马鱼心脏或哺乳动物心肌细胞中的表达会损害线粒体呼吸，并伴有 ROS 升高，导致心肌细胞凋亡和心力衰竭。相反，在成体小鼠心脏和斑马鱼中缺失 Hey2 会增强线粒体氧化基因的表达和心脏功能。多方面的全基因组分析表明，HEY2 富集在已知调控代谢的基因（包括 Ppargc1、Esrra 和 Cpt1）的启动子上，并与 HDAC1 共同作用，实现组蛋白去乙酰化和转录抑制。因此，在过表达 Hey2 的斑马鱼心脏或人类心肌细胞样细胞中恢复 PPARGC1A/ESRRA 能挽救线粒体生物能的缺陷。在成年小鼠心脏中敲除 Hey2 可防止多柔比星诱导的心脏功能障碍。这些研究揭示了一个进化保守的 HEY2/HDAC1-Ppargc1/Cpt 转录模块，它控制能量代谢以保护心脏功能。

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The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function.

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.