Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance.
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IF: 17.694
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Cited by: 41
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Datasets
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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.

Keywords

Seurat
Gene Expression
RNAscope
Spatial Transcriptomics

MeSH terms

Animals
Animals, Newborn
Cell Differentiation
Doxorubicin
Female
Heart
Heme Oxygenase (Decyclizing)
Humans
Induced Pluripotent Stem Cells
Male
Mice, Knockout
Mice, Transgenic
Myocardial Reperfusion Injury
Myocytes, Cardiac
NF-E2-Related Factor 1
Oxidation-Reduction
Proteostasis
Rats, Sprague-Dawley
Regeneration

Authors

Cui, Miao
Atmanli, Ayhan
Morales, Maria Gabriela
Tan, Wei
Chen, Kenian
Xiao, Xue
Xu, Lin
Liu, Ning
Bassel-Duby, Rhonda
Olson, Eric N

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