Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Rattus Norvegicus (ncbitaxon:10116)
SUBMITTER: 
Eric N. Olson
PROVIDER: MSV000087183 | MassIVE | Tue Apr 13 10:13:00 BST 2021
REPOSITORIES: MassIVE
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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 | GSE163628 | GEO
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 | GSE163630 | GEO
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.
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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.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2021-05-01 | GSE163631 | GEO
Project description:We addressed the question of which protein kinases are expressed in cardiomyocytes. We assessed the changes during postnatal development, comparing profiles in rat neonatal ventricular cardiomyocytes (NVMs) with adult ventricular cardiomyocytes (AVMs). Neonatal and adult rat ventricular cardiomyocytes prepared according to established procedures (Marshall et al. PLoS ONE 2010 5(4):e10027; Fuller and Sugden, FEBs Lett. 1989 247:209-12; Rodrigues and Severson In Biochemical Techniques in the Heart (McNeill, J. H., Ed.) pp 101-115, CRC Press, New York.). mRNA expression profiles compared using Affymetrix rat genome 230 2.0 arrays.
2015-01-01 | E-MTAB-2832 | biostudies-arrayexpress
Project description:Heart disease is the leading cause of death as there is no current method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish, larvae or adult, are able to regenerate their hearts via cardiomyocyte de-differentiation and proliferation. However, a molecular mechanism of why these cardiomyocytes can re-enter cell cycle is poorly understood. Here, we identify a unique metabolic state that primes adult zebrafish and neonatal mouse ventricular cardiomyocytes to proliferate. Zebrafish and neonatal mouse hearts display elevated glutamine levels, predisposing them to amino acid-driven activation of TOR. We show that this TOR activation is required for zebrafish cardiomyocyte regeneration in vivo. After injury we observe pS6 in both the epicardium and ventricular cardiomyocytes suggesting these are amino acid primed cells necessary for regeneration. Through single cell and system-wide RNA-sequencing, LQC proteomics and microscopy we identify dramatic metabolic and mitochondrial changes during the first week of regeneration. These data suggest that regeneration of zebrafish myocardium is driven by metabolic remodeling and reveals a unique metabolic regulator, TOR-primed state, in which zebrafish and mammalian cardiomyocytes are regeneration competent.
2022-01-11 | GSE184914 | GEO
Project description:Heart disease is the leading cause of death as there is no current method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish, larvae or adult, are able to regenerate their hearts via cardiomyocyte de-differentiation and proliferation. However, a molecular mechanism of why these cardiomyocytes can re-enter cell cycle is poorly understood. Here, we identify a unique metabolic state that primes adult zebrafish and neonatal mouse ventricular cardiomyocytes to proliferate. Zebrafish and neonatal mouse hearts display elevated glutamine levels, predisposing them to amino acid-driven activation of TOR. We show that this TOR activation is required for zebrafish cardiomyocyte regeneration in vivo. After injury we observe pS6 in both the epicardium and ventricular cardiomyocytes suggesting these are amino acid primed cells necessary for regeneration. Through single cell and system-wide RNA-sequencing, LQC proteomics and microscopy we identify dramatic metabolic and mitochondrial changes during the first week of regeneration. These data suggest that regeneration of zebrafish myocardium is driven by metabolic remodeling and reveals a unique metabolic regulator, TOR-primed state, in which zebrafish and mammalian cardiomyocytes are regeneration competent.
2022-01-11 | GSE188243 | GEO
Project description:miR-222 overexpression leads to promotion of proliferation and hypertrophy and inhibition of apoptosis in in primary neonatal rat ventricular cardiomyocytes (NRVMs). Isolated primary neonatal rat ventricular cardiomyocytes were plated in 6 cm BD Primaria tissue culture dishes. Transfection of microRNA precursors or scramble control (0.4 μM) was carried out using Lipofectamine RNAiMAX (Invitrogen) as recommended by the manufacturer. Forty-eight hours after transfection, RNAs from cultured cells and tissues were isolated with Tryzol (Invitrogen) following the manufacturesâ?? manuals. Total RNA was harvested and submitted to the Dana-Farber Cancer Institute Molecular Diagnostics Laboratory for assay. These results revealed miR-222 regulated gene expression in primary neonatal rat ventricular cardiomyocytes. Gene expression in NRVM cells tranfected with control scramble precursor (4 samples) or miR-222 precursor (4 smaples ) was evaluated using Affymetrix Rat Genome 230 v2.0.
2016-03-03 | E-GEOD-59641 | biostudies-arrayexpress
Project description:Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
| PRJNA686963 | ENA