TY - JOUR
T1 - Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
AU - Cui, Miao
AU - Atmanli, Ayhan
AU - Morales, Maria Gabriela
AU - Tan, Wei
AU - Chen, Kenian
AU - Xiao, Xue
AU - Xu, Lin
AU - Liu, Ning
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
N1 - Funding Information:
We thank Zhaoning Wang for contributing to the published snRNA-seq data generation; Dr. Gokhan S. Hotamisligil (Harvard University) for providing the Nrf1fl/fl mice; Jose Cabrera for graphics; Drs. Jian Xu and Yoon Jung Kim from the Children’s Research Institute at the University of Texas Southwestern Medical Center for performing the Illumina sequencing; Dr. Feng Wang for assistance analyzing the human patient datasets; Dr. Xiang Luo and Erica Niewold for help with isolating NRVMs; John Shelton from the Molecular Histopathology Core for help with histology; Dr. Andrew Lemoff from the Proteomics Core for help with the TMT proteomics analysis. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.vN.pN. M.C. is supported by a K99/ R00 pathway way to independence grant (NHLBI, K99HL153683). This work was supported by grants from the NIH (AR-067294, HL-130253, HL-138426, and HD-087351), the Foundation Leducq Transatlantic Networks of Excellence in Cardiovascular Research, and the Robert A. Welch Foundation (grant 1-0025 to E.N.O.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.
AB - Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.
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U2 - 10.1038/s41467-021-25653-w
DO - 10.1038/s41467-021-25653-w
M3 - Article
C2 - 34489413
AN - SCOPUS:85114635328
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5270
ER -