NR4All in the vessel wall

Tiel, Claudia M. van; Vries, Carlie J.M. de

doi:10.1016/j.jsbmb.2011.01.010

Cited by 42 publications

(41 citation statements)

References 51 publications

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“…Recently, the cardiovascular function of the NR4A receptor has received significant attention (14). Accumulating evidence suggests that NR4A receptors play essential roles in the development of atherosclerosis, restenosis, and angiogenesis (17,18,33).…”

Section: Discussionmentioning

confidence: 99%

“…So far, no ligands have been identified for these receptors, and therefore they are classified as orphan receptors. Recently, there has been much attention paid to the function of these receptors in cardiovascular system (14). In vascular smooth muscle cells, the expression of Nur77 and NOR-1 was significantly induced by atherogenic stimuli, such as platelet-derived growth factor BB, epidermal growth factor, and ␣-thrombin, and overexpression of Nur77 has been shown to inhibit cell proliferation and attenuate vascular injuryinduced neointimal formation in vivo (15,16).…”

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confidence: 99%

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Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Yan

Zhu

Huang

et al. 2015

Molecular and Cellular Biology

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The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (␤-AR) activation. However, the functional significance of Nur77 in ␤-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time-and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation of Nur77 in cardiomyocytes. Furthermore, cardiac overexpression of Nur77 by intramyocardial injection of Ad-Nur77 substantially inhibited cardiac hypertrophy and ameliorated cardiac dysfunction after chronic infusion of ISO in mice. Mechanistically, we demonstrated that Nur77 functionally interacts with NFATc3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy. These results demonstrate for the first time that Nur77 is a novel negative regulator for the ␤-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways. Targeting Nur77 may represent a potentially novel therapeutic strategy for preventing cardiac hypertrophy and heart failure. Cardiac hypertrophy is an adaptive process in response to various physiological or pathological stimuli associated with neurohumoral activation, elevated wall stress, and changes in volume load (1). Although initially adaptive, persistent hypertrophy induced by pathological conditions like myocardial infarction and hypertension has detrimental consequences on the heart and eventually progresses to heart failure, a major cause of death and disability in the industrialized world (1). At cellular and molecular levels, cardiac hypertrophy is characterized by increased myocyte size, sarcomerogenesis, and reexpression of a set of fetal genes, such as the atrial natriuretic factor, B-type natriuretic peptide, and ␤-myosin heavy chain genes, which are coordinately controlled by a subset of hypertrophy-responsive transcription factors, including myocyte enhancer factor 2 (MEF2), nuclear factor of activated T cells (NFAT), and GATA4 (2, 3) (4). Depending on the upstream hypertrophic stimuli, these transcriptional regulators can be directly phosphorylated or dephosphorylated by protein kinases, such as mitogen-activated protein (MAP) kinase and protein kinases A and C, as well as the calcium-activated phosphatase calcineurin, to facilitate hypertrophic gene expression (5-9). Disruption and/or attenuation of the activities of these transcription factors could serve as a potential therapeutic approach in terms of inhibiting the hypertrophic responses in the heart (10-12).NR4A receptors are immediate early genes that are regulated by various ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation

Yan

Zhu

Huang

et al. 2015

Molecular and Cellular Biology

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“…Nur77 is also known as NR4A1, TR3, or NGFI-B and is a member of the NR4A subfamily of nuclear receptors that are early response genes induced by diverse extracellular signals (16)(17)(18). Nur77 plays a pivotal role in the regulation of a wide range of biological processes, including cell proliferation, differentiation, and survival.…”

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confidence: 99%

“…Nur77 plays a pivotal role in the regulation of a wide range of biological processes, including cell proliferation, differentiation, and survival. Accumulating evidence suggests that Nur77 is implicated in the regulation of genes involved in metabolism, cancer, inflammation, and immunity and vascular disease (16)(17)(18)(19). In particular, Nur77 has been shown to have a protective function in restenosis and atherosclerosis (20,21).…”

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confidence: 99%

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Kurakula

Vos

Logiantara

et al. 2015

The Journal of Immunology

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Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we determined the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus production. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus production in lung epithelial cells. To further corroborate these findings, we searched for association of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing association with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.

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“…NR4A1 is involved in multiple molecular processes, including signal transmission, transcriptional regulation, mediation of cell growth, induction of apoptosis, and cell cycle control (Lee et al, 2011;McMorrow and Murphy, 2011;Mohan et al, 2012;van Tiel and de Vries, 2012). NR4A1 acts as a hormone receptor and is stimulated by ligand binding to move into the nucleus and associate with DNA to regulate transcription of multiple genes (Wu et al, 2002).…”

Section: Functionmentioning

confidence: 99%