TY - JOUR
T1 - The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis
AU - She, Peilu
AU - Gao, Bangjun
AU - Li, Dongliang
AU - Wu, Chen
AU - Zhu, Xuejiao
AU - He, Yuan
AU - Mo, Fei
AU - Qi, Yao
AU - Jin, Daqing
AU - Chen, Yewei
AU - Zhao, Xin
AU - Lin, Jinzhong
AU - Hu, Hairong
AU - Li, Jia
AU - Zhang, Bing
AU - Xie, Peng
AU - Lin, Chengqi
AU - Christoffels, Vincent M.
AU - Wu, Yueheng
AU - Zhu, Ping
AU - Zhong, Tao P.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85213869972
U2 - 10.1038/s41467-024-55557-4
DO - 10.1038/s41467-024-55557-4
M3 - 文章
C2 - 39747914
AN - SCOPUS:85213869972
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 232
ER -