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

Author

Listed:
  • Miao Cui

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Ayhan Atmanli

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Maria Gabriela Morales

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Wei Tan

    (University of Texas Southwestern Medical Center
    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
    University of Texas Southwestern Medical Center)

  • Rhonda Bassel-Duby

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Eric N. Olson

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • Miao Cui & Ayhan Atmanli & Maria Gabriela Morales & Wei Tan & Kenian Chen & Xue Xiao & Lin Xu & Ning Liu & Rhonda Bassel-Duby & Eric N. Olson, 2021. "Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25653-w
    DOI: 10.1038/s41467-021-25653-w
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    Cited by:

    1. Cornelis J. Boogerd & Ilaria Perini & Eirini Kyriakopoulou & Su Ji Han & Phit La & Britt Swaan & Jari B. Berkhout & Danielle Versteeg & Jantine Monshouwer-Kloots & Eva Rooij, 2023. "Cardiomyocyte proliferation is suppressed by ARID1A-mediated YAP inhibition during cardiac maturation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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