Cargando…

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

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,...

Descripción completa

Detalles Bibliográficos
Autores principales: Cui, Miao, Atmanli, Ayhan, Morales, Maria Gabriela, Tan, Wei, Chen, Kenian, Xiao, Xue, Xu, Lin, Liu, Ning, Bassel-Duby, Rhonda, Olson, Eric N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421386/
https://www.ncbi.nlm.nih.gov/pubmed/34489413
http://dx.doi.org/10.1038/s41467-021-25653-w
_version_ 1783749071969714176
author Cui, Miao
Atmanli, Ayhan
Morales, Maria Gabriela
Tan, Wei
Chen, Kenian
Xiao, Xue
Xu, Lin
Liu, Ning
Bassel-Duby, Rhonda
Olson, Eric N.
author_facet Cui, Miao
Atmanli, Ayhan
Morales, Maria Gabriela
Tan, Wei
Chen, Kenian
Xiao, Xue
Xu, Lin
Liu, Ning
Bassel-Duby, Rhonda
Olson, Eric N.
author_sort Cui, Miao
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8421386
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-84213862021-09-22 Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance Cui, Miao Atmanli, Ayhan Morales, Maria Gabriela Tan, Wei Chen, Kenian Xiao, Xue Xu, Lin Liu, Ning Bassel-Duby, Rhonda Olson, Eric N. Nat Commun Article 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. Nature Publishing Group UK 2021-09-06 /pmc/articles/PMC8421386/ /pubmed/34489413 http://dx.doi.org/10.1038/s41467-021-25653-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cui, Miao
Atmanli, Ayhan
Morales, Maria Gabriela
Tan, Wei
Chen, Kenian
Xiao, Xue
Xu, Lin
Liu, Ning
Bassel-Duby, Rhonda
Olson, Eric N.
Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
title Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
title_full Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
title_fullStr Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
title_full_unstemmed Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
title_short Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
title_sort nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421386/
https://www.ncbi.nlm.nih.gov/pubmed/34489413
http://dx.doi.org/10.1038/s41467-021-25653-w
work_keys_str_mv AT cuimiao nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT atmanliayhan nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT moralesmariagabriela nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT tanwei nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT chenkenian nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT xiaoxue nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT xulin nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT liuning nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT basseldubyrhonda nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance
AT olsonericn nrf1promotesheartregenerationandrepairbyregulatingproteostasisandredoxbalance