The NR4A orphan nuclear receptors: mediators in metabolism and diseases

Ranhotra, Harmit S.

doi:10.3109/10799893.2014.948555

Cited by 60 publications

(57 citation statements)

References 36 publications

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“…An increasing number of studies have demonstrated that NR4A receptors play important roles in the development of various cardiovascular diseases, including atherosclerosis, restenosis, angiogenesis, and heart failure (32,34,36). Previously, our studies identified Nur77 as a novel negative regulator for the β-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways (28).…”

Section: Discussionmentioning

confidence: 81%

Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist–induced apoptosis in cardiomyocytes

You

Guo

Fang

et al. 2018

Journal of Biological Chemistry

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The relaxin family peptides have been shown to exert several beneficial effects on the heart, including anti-apoptosis, anti-fibrosis, and antihypertrophy activity. Understanding their regulation might provide new opportunities for therapeutic interventions, but the molecular mechanism(s) coordinating relaxin expression in the heart remain largely obscured. Previous work demonstrated a role for the orphan nuclear receptor Nur77 in regulating cardiomyocyte apoptosis. We therefore investigated Nur77 in the hopes of identifying novel relaxin regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) data indicated that ectopic expression of orphan nuclear receptor Nur77 markedly increased the expression of latexin-3 (RLN3), but not relaxin-1 (RLN1), in neonatal rat ventricular cardiomyocytes (NRVMs). Furthermore, we found that the beta-adrenergic agonist isoproterenol (ISO) markedly stimulated RLN3 expression, and this stimulation was significantly attenuated in Nur77 knockdown cardiomyocytes and Nur77 knockout hearts. We showed that Nur77 significantly increased RLN3 promoter activity via specific binding to the RLN3 promoter, as demonstrated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. Furthermore, we found that Nur77 overexpression potently inhibited ISO-induced cardiomyocyte apoptosis, while this protective effect was significantly attenuated in RLN3 knockdown cardiomyocytes, suggesting that Nur77-induced RLN3 expression is an important mediator for the suppression of cardiomyocyte apoptosis. These findings show that Nur77 regulates RLN3 expression, therefore suppressing apoptosis in the heart, and suggest that activation of Nur77 may represent a useful therapeutic strategy for inhibition of cardiac fibrosis and heart failure. Upregulation of Relaxin-3 by Nur77 2The relaxin peptide family in humans consists of seven members, relaxin-1 (H1 relaxin), relaxin-2 (H2 relaxin), relaxin-3 (H3 relaxin) and insulin-like (INSL) peptides (1). Like insulin, relaxin consists of two peptide chains, A and B, covalently linked by disulfide bonds. Through binding to the relaxin family peptide (RXFP) receptors, the relaxin peptide has been shown to initiate a wide range of biological effects in various systems, including regulation of cell survival, proliferation, vessel relaxation, inflammation, and fibrosis (1) (2) (3) (4). Humans (and higher primates) have three relaxin genes, designated H1, H2, and H3 relaxin, while rodents have two genes, relaxin (equivalent to H2 relaxin) and relaxin-3 (equivalent to H3 relaxin) (5). H2 relaxin is the major source of circulating relaxin. Four relaxin family peptide receptors (RXFP1-4) have been identified (6) (7). H2 relaxin is a ligand for receptors RXFP1 and RXFP2, whereas H3 relaxin is the ligand for RXFP3, but also crossreacts with RXFP1 and RXFP4 (6). Despite the physiological significance of relaxin in the reproductive and central nervous systems, the cardiovascular effects of relaxin have...

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Section: Discussionmentioning

confidence: 81%

Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist–induced apoptosis in cardiomyocytes

You

Guo

Fang

et al. 2018

Journal of Biological Chemistry

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“…Organ damage Apoptosis Senescence disease notably diabetes, Parkinson and cardiovascular disease [24,28,40,41]. Several points of evidence underly the role of NR4A receptors in metabolic syndrome and diabetes.…”

Section: Metabolic Alteraɵonsmentioning

confidence: 99%

The NR4A nuclear receptors as potential targets for anti-aging interventions

Paillasse¹,

Médina²

2015

Medical Hypotheses

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“…They were first identified molecularly as immediate-early response genes [212]. Much of the work on this gene class has focused on cell biological studies of their role in metabolism, cell cycle control, and apoptosis [213-215]. Nur77 interacts with RXR and p53 to regulate genes associated the cellular proliferation and participates with RXR and Bcl-2 in regulating apoptosis via a non-transcriptional pathway [214].…”

Section: Hr38/nhr-6/nur77/nurr1/nor1 (Nr4a)mentioning

confidence: 99%

Conserved and Exapted Functions of Nuclear Receptors in Animal Development

Bodofsky¹,

Koitz²,

Wightman³

2017

Nuclear Receptor Research

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The nuclear receptor gene family includes 18 members that are broadly conserved among multiple disparate animal phyla, indicating that they trace their evolutionary origins to the time at which animal life arose. Typical nuclear receptors contain two major domains: a DNA-binding domain and a C-terminal domain that may bind a lipophilic hormone. Many of these nuclear receptors play varied roles in animal development, including coordination of life cycle events and cellular differentiation. The well-studied genetic model systems of Drosophila, C. elegans, and mouse permit an evaluation of the extent to which nuclear receptor function in development is conserved or exapted (repurposed) over animal evolution. While there are some specific examples of conserved functions and pathways, there are many clear examples of exaptation. Overall, the evolutionary theme of exaptation appears to be favored over strict functional conservation. Despite strong conservation of DNA-binding domain sequences and activity, the nuclear receptors prove to be highly-flexible regulators of animal development.

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The NR4A orphan nuclear receptors: mediators in metabolism and diseases

Cited by 60 publications

References 36 publications

Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist–induced apoptosis in cardiomyocytes

Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist–induced apoptosis in cardiomyocytes

The NR4A nuclear receptors as potential targets for anti-aging interventions

Conserved and Exapted Functions of Nuclear Receptors in Animal Development

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