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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE163631 | GEO | 2021/05/01

REPOSITORIES: GEO

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

Project 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.

| S-EPMC8421386 | biostudies-literature

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [Spatial transcriptome]

Project description:Heart disease can be caused by ischemic coronary artery injury, hypertension, and chemotherapy, all of which lead to loss or dysfunction of cardiac muscle. The adult mammalian heart lacks the ability to regenerate. In contrast, the heart of neonatal mice, within the first week after birth, possesses a unique ability to regenerate lost myocardium following injury, mediated by proliferation of cardiomyocytes. The mechanisms whereby neonatal cardiomyocytes adapt to injury-induced stress conditions and activate regenerative cellular programs remain to be defined. Here, we show that Nrf1, an endoplasmic reticulum (ER) bound transcription factor, is expressed in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented cardiomyocytes from activating a transcriptional program required for heart regeneration, revealed by single-nucleus RNA sequencing (snRNA-seq). Conversely, adeno-associated virial (AAV) overexpression of Nrf1 protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) from doxorubicin-induced cardiotoxicity. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal a mechanistic interplay between adaptive stress responses and heart regeneration, and highlight the central role of Nrf1 in these processes.

2021-05-01 | GSE163629 | GEO

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [scRNA-Seq]

2021-05-01 | GSE163630 | GEO

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [bulkRNA-Seq]

2021-05-01 | GSE163628 | GEO

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

Project description:Ten million neonatal rat ventricular cardiomyocytes were infected with adenovirus to overexpress NRF1 or LacZ (control). 48 hours after infection, cells were collected and lysed for TMT proteomic analysis.

2021-04-13 | MSV000087183 | MassIVE

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

Project description:Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

| PRJNA686963 | ENA

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [bulkRNA-Seq]

Project description:Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [bulkRNA-Seq]

| PRJNA686966 | ENA

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [scRNA-Seq]

Project description:Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [scRNA-Seq]

| PRJNA686967 | ENA

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [Spatial transcriptome]

Project description:Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [Spatial transcriptome]

| PRJNA686968 | ENA

Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy.

Project description:Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1-dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

| S-EPMC8759782 | biostudies-literature

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