Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

Miao Cui, Ayhan Atmanli, Maria Gabriela Morales, Wei Tan, Kenian Chen, Xue Xiao, Lin Xu, Ning Liu, Rhonda Bassel-Duby and Eric N. Olson ()
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Miao Cui: University of Texas Southwestern Medical Center
Ayhan Atmanli: University of Texas Southwestern Medical Center
Maria Gabriela Morales: University of Texas Southwestern Medical Center
Wei Tan: University of Texas Southwestern Medical Center
Kenian Chen: University of Texas Southwestern Medical Center
Xue Xiao: University of Texas Southwestern Medical Center
Lin Xu: University of Texas Southwestern Medical Center
Ning Liu: University of Texas Southwestern Medical Center
Rhonda Bassel-Duby: University of Texas Southwestern Medical Center
Eric N. Olson: University of Texas Southwestern Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25653-w

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