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

Cui, Miao; Atmanli, Ayhan; Morales, María Gabriela; Wang, Tan; Chen, Kenian; Xiao, Xue; Xu, Lin; Liu, Ning; Bassel‐Duby, Rhonda; Olson, Eric N.

doi:10.1038/s41467-021-25653-w

Cited by 85 publications

(79 citation statements)

References 60 publications

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“…55, 56 HMOX1 is an important activator of NRF1, which has been recently discovered to be involved in heart regeneration and repair, promoted by NRF1 signaling. 57 Importantly, four members of the family of glutathione peroxidases involved in the termination reaction of ROS pathways were increased in TG AC8 vs WT: Gpx3 (transcripts by 103%, proteins by 30%); Gpx7 (transcripts by 40%, proteins by 21%); Gpx8 (transcripts by 20%, proteins by 16%); Gpx1 (transcripts by 39%, proteins by 12%). Several members of glutathione transferases were differentially expressed in TG AC8 vs WT: Gsta3 (transcripts and proteins upregulated by 55% and 26% respectively); GSTM5 (proteins upregulated by 23%), GSTM1 (proteins upregulated by 14%); mitochondrial glutathione reductase GSR was also upregulated, while GSTM7 (transcripts and proteins were decreased by 21%, and 9%) and GSTO1 (protein was decreased by 9%).…”

Section: Discussionmentioning

confidence: 94%

Section: Ros Regulationmentioning

confidence: 94%

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A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

Tarasov

Chakir

Riordon

et al. 2022

Preprint

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Adult mice with a marked increase in Adenylyl cyclase (AC) activity due to cardio-specific over expression of adenylyl cyclase (AC) type VIII (TGAC8) have an incessantly cardiac work load adapt to this chronic, severe cAMP stress for up to a year without signs of heart failure and without excessive mortality compared to wild-type littermates (WT). Here we focused on mechanisms that underly the TGAC8 adaptive paradigm.Although TGAC8 mice had a 30% increase in both HR and cardiac output, a 23% increase in EF (echocardiography), neither total LV mass nor pathologic hypertrophy biomarkers differed by genotype. Compared to WT the LV cavity volume was reduced in TGAC8, but was encased by thicker LV walls, harboring populations of both smaller cardiac myocytes, and small non-cardiac interstitial cells having increased nuclear EdU labeling. Protein synthesis, proteosome activity, autophagy, Nrf-2 and Hsp90α proteins were also increased in TGAC8 vs WT, but super-oxide radicals did not differ. Despite an apparently marked increased energy demand due to a chronically increased cardiac workload in the context of a chronically increased HR and EF, steady-state LV ATP and phosphocreatine in vivo did not differ in TGAC8 vs WT. Further Acc2, known to suppress fatty acid oxidation and to increase aerobic glycolysis in the context of enhanced utilization of the pentose phosphate shunt, and NADH/NADPH cycling were both elevated in TGAC8 vs WT mice.Unbiased omics unveiled additional genotypic differences in the potential mechanisms involved in the chronically increased TGAC8 heart performance and the adaptive paradigm in response to this chronic stress. 2,323 transcripts and 2,184 proteins, spanning a wide array of biological processes and molecular functions in numerous cellular compartments, including over 250 canonical signaling pathways, that integrate stress responses, cytokine and T cell receptor signaling, immune responses, ROS scavenging, protection from apoptosis, and nutrient sensing, were activated in TGAC8 vs WT. Several adaptive mechanisms that limit cAMP/PKA signaling were also activated in TGAC8.Thus, in addition to markedly increased cardiac work, the chronic, intense AC-PKA-Ca2+ signaling within the adult TGAC8 heart concurrently activates a consilience of adaptive mechanisms within the TGAC8 LV that resemble survival mechanisms within cancer cells.

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Section: Discussionmentioning

confidence: 94%

Section: Ros Regulationmentioning

confidence: 94%

A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

Tarasov

Chakir

Riordon

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, SIRT1 can deacetylate PGC-1α, activating a suite of genes [50] involved in mitochondrial function and biogenesis, such as nuclear respiratory factor-1 (Nrf1) [49,53]. Consistent with this, a recent study showed that NRF1 could protect human-induced pluripotent stem cells (hiPSC)-derived cardiomyocytes against a range of cardiotoxins, including DOX [54]. In summary, sirtuins can regulate mitochondrial function and thereby promote cardiomyocyte survival.…”

Section: Dox Accumulates In the Mitochondria And Perturbs Mitochondri...mentioning

confidence: 74%

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Leung

Poon

2022

IJMS

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Anthracyclines, such as doxorubicin, are effective chemotherapeutic agents for the treatment of cancer, but their clinical use is associated with severe and potentially life-threatening cardiotoxicity. Despite decades of research, treatment options remain limited. The mitochondria is commonly considered to be the main target of doxorubicin and mitochondrial dysfunction is the hallmark of doxorubicin-induced cardiotoxicity. Here, we review the pathogenic mechanisms of doxorubicin-induced cardiotoxicity and present an update on cardioprotective strategies for this disorder. Specifically, we focus on strategies that can protect the mitochondria and cover different therapeutic modalities encompassing small molecules, post-transcriptional regulators, and mitochondrial transfer. We also discuss the shortcomings of existing models of doxorubicin-induced cardiotoxicity and explore advances in the use of human pluripotent stem cell derived cardiomyocytes as a platform to facilitate the identification of novel treatments against this disorder.

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“…For example, scRNA-seq can confirm and enrich the regional gene expression data obtained by spRNA-seq to generate a 3D atlas of the human embryonic heart (Asp et al, 2019). Similarly, by combining scRNA-seq and spRNA-seq, one subpopulation of cardiomyocytes overexpressing Nrf1 has been identified near the infarcted region of the heart (Cui et al, 2021). Thus, the activation of the Nrf1 pathway represents a new therapeutic approach for cardiac injury.…”

Section: Scrna-seq and Bulk And Spatial Rna Sequencingmentioning

confidence: 99%

Applications of Single-Cell RNA Sequencing in Cardiovascular Research

Fan

Han

Liu

et al. 2022

Front. Cell Dev. Biol.

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In recent years, cardiovascular disease (CVD) continues to be the leading cause of global disease burden. Extensive efforts have been made across basic, translational, and clinical research domains to curb the CVD epidemic and improve the health of the population. The successful completion of the Human Genome Project catapulted sequencing technology into the mainstream and aroused the interests of clinicians and scientific researchers alike. Advances in single-cell RNA sequencing (scRNA-seq), which is based on the transcriptional phenotypes of individual cells, have enabled the investigation of cellular fate, heterogeneity, and cell–cell interactions, as well as cell lineage determination, at a single-cell resolution. In this review, we summarize recent findings on the embryological development of the cardiovascular system and the pathogenesis and treatment of cardiovascular disease, as revealed by scRNA-seq technology. In particular, we discuss how scRNA-seq can help identify potential targets for the treatment of cardiovascular diseases and conclude with future perspectives for scRNA-seq.

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

Cited by 85 publications

References 60 publications

A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

Applications of Single-Cell RNA Sequencing in Cardiovascular Research

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