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Carlie J M De Vries - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes.
International journal of molecular sciences, 2021Co-Authors: Lejla Medzikovic, Carlie J M De Vries, Pieter B. Van Loenen, Hylja Heese, Cindy P. A. A. Van Roomen, Ingeborg B. Hooijkaas, Vincent M. Christoffels, Esther E. Creemers, Vivian De WaardAbstract:Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear Receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor–β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β Receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis.
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‘Nur'turing tumor T cell tolerance and exhaustion: novel function for Nuclear Receptor Nur77 in immunity
European journal of immunology, 2020Co-Authors: Sanne C. Lith, Bram W. Van Os, Tom T.p. Seijkens, Carlie J M De VriesAbstract:The Nuclear Receptor Nur77 is expressed in a multitude of tissues, regulating cell differentiation and homeostasis. Dysregulation of Nur77 signaling is associated with cancer, cardiovascular disease, and disorders of the CNS. The role of Nur77 in T cells has been studied for almost 30 years now. There is a clear appreciation that Nur77 is crucial for apoptosis of self-reactive T cells. However, the regulation and function of Nur77 in mature T cells remains largely unclear. In an exciting development, Nur77 has been recently demonstrated to impinge on cancer immunotherapy involving chimeric antigen Receptor (CAR) T cells and tumor infiltrating lymphocytes (TILs). These studies indicated that Nur77 deficiency reduced T cell tolerance and exhaustion, thus raising the effectiveness of immune therapy in mice. Based on these novel insights, it may be proposed that regulation of Nur77 activity holds promise for innovative drug development in the field of cellular immunotherapy in cancer. In this review, we therefore summarize the role of Nur77 in T cell selection and maturation; and further develop the idea of targeting its activity in these cells as a potential strategy to augment current cancer immunotherapy treatments.
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Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells
Journal of immunology (Baltimore Md. : 1950), 2015Co-Authors: Kondababu Kurakula, Mariska Vos, A. Logiantara, Joris J. T. H. Roelofs, Maartje A.e. Nieuwenhuis, Gerard H. Koppelman, Dirkje S. Postma, Leonie S. Van Rijt, Carlie J M De VriesAbstract: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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Limited Role of Nuclear Receptor Nur77 in Escherichia coli-Induced Peritonitis
Infection and immunity, 2013Co-Authors: Anouk A J Hamers, Carlie J M De Vries, Claudia M. Van Tiel, Stephan Huveneers, Sven Uleman, Daniëlle Kruijswijk, Anne-marieke D. Van Stalborch, Cornelis Van 't VeerAbstract:Nuclear Receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to play an anti-inflammatory role in macrophages, which have a crucial function in defense against peritonitis. The function of Nur77 in Escherichia coli-induced peritoneal sepsis has not yet been investigated. Wild-type and Nur77-knockout mice were inoculated with E. coli, and bacterial outgrowth, cell recruitment, cytokine profiles, and tissue damage were investigated. We found only a minor transient decrease in bacterial loads in lung and liver of Nur77-knockout compared to wild-type mice at 14 h postinfection, yet no changes were found in the peritoneal lavage fluid or blood. No differences in inflammatory cytokine levels or neutrophil/macrophage numbers were observed, and bacterial loads were equal in wild-type and Nur77-knockout mice at 20 h postinfection in all body compartments tested. Also, isolated peritoneal macrophages did not show any differences in cytokine expression patterns in response to E. coli. In endothelial cells, Nur77 strongly downregulated both protein and mRNA expression of claudin-5, VE-cadherin, occludin, ZO-1, and β-catenin, and accordingly, these genes were upregulated in lungs of Nur77-deficient mice. Functional permeability tests pointed toward a strong role for Nur77 in endothelial barrier function. Indeed, tissue damage in E. coli-induced peritonitis was notably modulated by Nur77; liver necrosis and plasma aspartate aminotransferase (ASAT)/alanine aminotransferase (ALAT) levels were lower in Nur77-knockout mice. These data suggest that Nur77 does not play a role in the host response to E. coli in the peritoneal and blood compartments. However, Nur77 does modulate bacterial influx into the organs via increased vascular permeability, thereby aggravating distant organ damage.
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abstract 471 Nuclear Receptor Nur77 reduces atherosclerosis
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Anouk A J Hamers, Menno P J De Winther, Marion J J Gijbels, Vivian De Waard, Carlie J M De VriesAbstract:Rationale: Nuclear Receptor Nur77, also known as NR4A1, TR3 or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. Objective: This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis. Methods and results: We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77 -/- )-mice (n=10). Nur77 -/- BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of IL12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77 -/- BMM cells. SDF-1α expression in non-stimulated Nur77 -/- BMM is repressed by Nur77 and the chemoattractive activity of Nur77 -/- BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77 -/- mice show enhanced thioglycollate-elicited migration of macrophages and B-cells. The effect of bone marrow-specific deficiency of Nur77 on atherosclerosis was studied in low density lipoprotein Receptor-deficient (Ldlr -/- ) mice. Ldlr -/- mice with a Nur77 -/- -deficient bone marrow transplant develop 2.1-fold larger atherosclerotic lesions than wild-type bone marrow transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77 -/- -transplanted mice, which may explain the observed aggravation of lesion formation. Conclusions: In conclusion, in bone-marrow derived cells the Nuclear Receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
Xiaolei Wang - One of the best experts on this subject based on the ideXlab platform.
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Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin
Hypertension (Dallas Tex. : 1979), 2015Co-Authors: Mingli Cui, Zhaohua Cai, Zhe Sun, Shichun Chu, Xiaolei Wang, Ling-hong ShenAbstract:Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan Nuclear Receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases.
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abstract 12813 orphan Nuclear Receptor Nur77 inhibits angiotensin ii induced vascular remodeling via downregulation of β catenin activity
Circulation, 2015Co-Authors: Mingli Cui, Zhaohua Cai, Peng Nie, Zhe Sun, Shiqun Sun, Shichun Chu, Xiaolei Wang, Ling-hong ShenAbstract:Background: Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system (RAS). Ang II contributes to vascular remodeling in many cardiovascular diseases (e.g., hypertension, atherosclerosis, restenosis, and aneurysm). Orphan Nuclear Receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Methods and Results: Male Nur77-/- and wildtype (WT) littermate control mice (12-16 weeks of age) were continuously infused with Ang II using a mini-osmotic pump. Nur77 expression was increased in medial vascular smooth muscle cells (VSMCs) of thoracic aorta from WT mice after 2 weeks of exogenous Ang II administration. Loss of Nur77 resulted in enhanced outward vascular remodeling as reflected by increased medial area (197000±7091 μm2 vs. 174000±5927 μm2, p<0.05) and luminal diameter (880.7±24.13 μm vs. 825.2±10.38 μm, p<0.05), and more severe elastin disrup...
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The orphan Nuclear Receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice
International journal of molecular medicine, 2015Co-Authors: Zhaohua Cai, Mingli Cui, Peng Nie, Zhe Sun, Shiqun Sun, Shichun Chu, Xiaolei WangAbstract:Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan Nuclear Receptor Nur77 [also known as TR3 or Nuclear Receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77‑deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell Nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling.
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GW26-e2456 Orphan Nuclear Receptor Nur77 deletion exacerbates low shear stress-induced carotid artery remodeling in mice
Journal of the American College of Cardiology, 2015Co-Authors: Zhaohua Cai, Mingli Cui, Peng Nie, Zhe Sun, Shiqun Sun, Shichun Chu, Xiaolei WangAbstract:Carotid artery remodeling, also defined as intima-media thickening, is an important predictive indicator for human cardiovascular disease. Chronic changes in shear stress contribute to vascular remodeling. Orphan Nuclear Receptor Nur77 is expressed in diseased human vascular tissue, and plays a
Keesook Lee - One of the best experts on this subject based on the ideXlab platform.
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Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77
PloS one, 2014Co-Authors: Eunsook Park, Hueng-sik Choi, Jae-il Park, Chin Hee Song, Ryun Sup Ahn, Keesook LeeAbstract:Transforming growth factor- β1 (TGF-β1) has been reported to inhibit luteinizing hormone (LH) mediated-steroidogenesis in testicular Leydig cells. However, the mechanism by which TGF-β1 controls the steroidogenesis in Leydig cells is not well understood. Here, we investigated the possibility that TGF-β1 represses steroidogenesis through cross-talk with the orphan Nuclear Receptor Nur77. Nur77, which is induced by LH/cAMP signaling, is one of major transcription factors that regulate the expression of steroidogenic genes in Leydig cells. TGF-β1 signaling inhibited cAMP-induced testosterone production and the expression of steroidogenic genes such as P450c17, StAR and 3β-HSD in mouse Leydig cells. Further, TGF-β1/ALK5 signaling repressed cAMP-induced and Nur77-activated promoter activity of steroidogenic genes. In addition, TGF-β1/ALK5-activated Smad3 repressed Nur77 transactivation of steroidogenic gene promoters by interfering with Nur77 binding to DNA. In primary Leydig cells isolated from Tgfbr2flox/flox Cyp17iCre mice, TGF-β1-mediated repression of cAMP-induced steroidogenic gene expression was significantly less than that in primary Leydig cells from Tgfbr2flox/flox mice. Taken together, these results suggest that TGF-β1/ALK5/Smad3 signaling represses the expression of steroidogenic genes via the suppression of Nur77 transactivation in testicular Leydig cells. These findings may provide a molecular mechanism involved in the TGF-β1-mediated repression of testicular steroidogenesis.
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Anti-steroidogenic Factor ARR19 Inhibits Testicular Steroidogenesis through the Suppression of Nur77 Transactivation
The Journal of biological chemistry, 2010Co-Authors: Imteyaz Qamar, Chin Hee Song, Eun-yeung Gong, Yeawon Kim, Hyun Joo Lee, Sang-young Chun, Keesook LeeAbstract:ARR19 (androgen Receptor corepressor-19 kDa), a leucine-rich protein whose expression is down-regulated by luteinizing hormone and cAMP, is differentially expressed during the development of Leydig cells and inhibits testicular steroidogenesis by reducing the expression of steroidogenic enzymes. However, the molecular events behind the suppression of testicular steroidogenesis are unknown. In the present study, we demonstrate that ARR19 inhibits the transactivation of orphan Nuclear Receptor Nur77, which is one of the major transcription factors that regulate the expression of steroidogenic enzyme genes in Leydig cells. ARR19 physically interacts with Nur77 and suppresses Nur77-induced promoter activity of steroidogenic enzyme genes including StAR, P450c17, and 3beta-HSD in Leydig cells. Transient transfection and chromatin immunoprecipitation assays revealed that ARR19-mediated reduced expression of steroidogenic enzyme genes was likely due to the interference of SRC-1 recruitment to Nur77 protein on the promoter of steroidogenic enzyme genes. These findings suggest that ARR19 acts as a novel coregulator of Nur77, in turn regulating Nur77-induced testicular steroidogenesis, and may play an important role in the development and function of testicular Leydig cells.
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Orphan Nuclear Receptor Nur77 Induces Zinc Finger Protein GIOT-1 Gene Expression, and GIOT-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor SF-1 via Recruitment of HDAC2
The Journal of biological chemistry, 2006Co-Authors: Kwang-hoon Song, Keesook Lee, Cheol Yi Hong, Yun-yong Park, Hae Jin Kee, Yong-soo Lee, Seung-won Ahn, Hye Jin Kim, Hyun Kook, In-kyu LeeAbstract:Kruppel-associated box (KRAB) domain-containing proteins consist of potential transcriptional repression modules. Previously, gonadotropin-inducible ovarian transcription factor-1 (GIOT-1) was identified as a novel KRAB-containing zinc finger protein and shown to have transcriptional repression activity. Here, we demonstrate that orphan Nuclear Receptor Nur77 regulates GIOT-1 gene expression in testicular Leydig cell lines and that GIOT-1 acts as a novel corepressor of the orphan Nuclear Receptor steroidogenic factor 1 (SF-1). Mutation analysis of the GIOT-1 promoter and overexpression analysis of dominant-negative Nur77 revealed that luteinizing hormone activates GIOT-1 gene expression through Nur77. Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that Nur77 directly binds to the GIOT-1 promoter. GIOT-1 represses the SF-1 transactivation, and specific interaction between GIOT-1 and SF-1 was observed. We also demonstrate an interaction between GIOT-1 and histone deacetylase 2 (HDAC2). GIOT-1-mediated transrepression was recovered by down-regulation of HDAC2 expression with small interfering RNA of HDAC2. Knock down of the endogenous GIOT-1 results in significant enhancement of CYP17 expression in Leydig cells. In conclusion, this study of cross-talk between GIOT-1 and orphan Nuclear Receptors will provide new insights into the role of KRAB-containing zinc finger proteins in Nuclear Receptor action.
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The Atypical Orphan Nuclear Receptor DAX-1 Interacts with Orphan Nuclear Receptor Nur77 and Represses Its Transactivation
Molecular endocrinology (Baltimore Md.), 2004Co-Authors: Kwang-hoon Song, Keesook Lee, Ki Cheol Park, Yun-young Park, Cheol Yi Hong, Jin Hee Park, Minho Shong, Hueng-sik ChoiAbstract:DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome, gene 1) (NROB1) is an atypical member of the Nuclear Receptor family, which lacks the classical zinc finger DNA binding domain and acts as a coregulator of a number of Nuclear Receptors. In this study, we have found that DAX-1 is a novel coregulator of the orphan Nuclear Receptor Nur77 (NR4A1). We demonstrate that DAX-1 represses the Nur77 transactivation by transient transfection assays. Specific interaction between Nur77 and DAX-1 was detected by coimmunoprecipitation, yeast two-hybrid, and glutathione-S-transferase pull-down assays. The ligand binding domain of DAX-1 and the activation function-2 domain of Nur77 were determined as the direct interaction domains between DAX-1 and Nur77. In vitro competition binding assay showed that DAX-1 repressed Nur77 transactivation through the competition with steroid Receptor coactivator-1 for the binding of Nur77. Moreover, DAX-1 repressed Nur77- and LH-dependent increase of cytochrome P450 protein 17 promoter activity in transient transfection assays. Furthermore, Nur77-mediated transactivation was significantly increased by down-regulation of DAX-1 expression with DAX-1 small interfering RNA in testicular Leydig cell line, K28. LH treatment induced a transient increase in Nur77 mRNA, whereas LH repressed DAX-1 expression in a time- and dose-dependent manner in K28 cells. In addition, immunohistochemical analysis showed the expression of Nur77 in mouse testicular Leydig cells. These results suggest that DAX-1 acts as a novel coregulator of the orphan Nuclear Receptor Nur77, and that the DAX-1 may play a key role in the regulation of Nur77-mediated steroidogenesis in testicular Leydig cells.
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Endocrine disrupter bisphenol a induces orphan Nuclear Receptor Nur77 gene expression and steroidogenesis in mouse testicular Leydig cells.
Endocrinology, 2002Co-Authors: Kwang-hoon Song, Keesook Lee, Hueng-sik ChoiAbstract:The orphan Nuclear Receptor Nur77 (NR4A1) is a member of the Nuclear Receptor superfamily, which plays an important role in the regulation of LH-mediated steroidogenesis in testicular Leydig cells. The aim of the current study was to investigate the potential role of bisphenol A (BPA) on orphan Nuclear Receptor Nur77 gene expression and steroidogenesis. Northern blot analysis demonstrated that BPA transiently induced Nur77 mRNA expression, and protein kinase inhibitor H-89 and PD98059 strongly inhibited the induction of BPA-mediated Nur77 gene expression in mouse Leydig tumor cell line, K28. Moreover, BPA increased the activation of mitogen-activated protein kinase. Transient transfection assay demonstrated that BPA increased Nur77 gene promoter activity and Nur77 transactivation, whereas BPA did not significantly affect the interaction of Nur77 with its corepressor. Furthermore, BPA increased progesterone biosynthesis in K28 cells, which was suppressed by overexpression of dominant negative Nur77. Finall...
Zhaohua Cai - One of the best experts on this subject based on the ideXlab platform.
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Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin
Hypertension (Dallas Tex. : 1979), 2015Co-Authors: Mingli Cui, Zhaohua Cai, Zhe Sun, Shichun Chu, Xiaolei Wang, Ling-hong ShenAbstract:Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan Nuclear Receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases.
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abstract 12813 orphan Nuclear Receptor Nur77 inhibits angiotensin ii induced vascular remodeling via downregulation of β catenin activity
Circulation, 2015Co-Authors: Mingli Cui, Zhaohua Cai, Peng Nie, Zhe Sun, Shiqun Sun, Shichun Chu, Xiaolei Wang, Ling-hong ShenAbstract:Background: Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system (RAS). Ang II contributes to vascular remodeling in many cardiovascular diseases (e.g., hypertension, atherosclerosis, restenosis, and aneurysm). Orphan Nuclear Receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Methods and Results: Male Nur77-/- and wildtype (WT) littermate control mice (12-16 weeks of age) were continuously infused with Ang II using a mini-osmotic pump. Nur77 expression was increased in medial vascular smooth muscle cells (VSMCs) of thoracic aorta from WT mice after 2 weeks of exogenous Ang II administration. Loss of Nur77 resulted in enhanced outward vascular remodeling as reflected by increased medial area (197000±7091 μm2 vs. 174000±5927 μm2, p<0.05) and luminal diameter (880.7±24.13 μm vs. 825.2±10.38 μm, p<0.05), and more severe elastin disrup...
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The orphan Nuclear Receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice
International journal of molecular medicine, 2015Co-Authors: Zhaohua Cai, Mingli Cui, Peng Nie, Zhe Sun, Shiqun Sun, Shichun Chu, Xiaolei WangAbstract:Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan Nuclear Receptor Nur77 [also known as TR3 or Nuclear Receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77‑deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell Nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling.
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GW26-e2456 Orphan Nuclear Receptor Nur77 deletion exacerbates low shear stress-induced carotid artery remodeling in mice
Journal of the American College of Cardiology, 2015Co-Authors: Zhaohua Cai, Mingli Cui, Peng Nie, Zhe Sun, Shiqun Sun, Shichun Chu, Xiaolei WangAbstract:Carotid artery remodeling, also defined as intima-media thickening, is an important predictive indicator for human cardiovascular disease. Chronic changes in shear stress contribute to vascular remodeling. Orphan Nuclear Receptor Nur77 is expressed in diseased human vascular tissue, and plays a
Mariska Vos - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism
Cell reports, 2018Co-Authors: Duco S. Koenis, Mariska Vos, Lejla Medzikovic, Pieter B. Van Loenen, Michel Van Weeghel, Stephan Huveneers, Ingrid Johanna Evers-van Gogh, Jan Van Den Bossche, Dave Speijer, Yongsoo KimAbstract:Summary Activation of macrophages by inflammatory stimuli induces reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines and nitric oxide. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation by isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the Nuclear Receptor Nur77 (Nr4a1) as a key upstream transcriptional regulator of this pro-inflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other TCA cycle-derived metabolites in response to inflammatory stimulation in a glutamine-independent manner. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased circulating succinate levels. In summary, Nur77 induces an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis.
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Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages.
PloS one, 2015Co-Authors: Anouk A J Hamers, Mariska Vos, Goran Marinković, Claudia M. Van Tiel, Stephan Huveneers, Anne-marieke D. Van Stalborch, Laura S. Van Dam, Jose Duarte, Sybren L. Meijer, Anje A. Te VeldeAbstract:Nuclear Receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn’s disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases.
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Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells
Journal of immunology (Baltimore Md. : 1950), 2015Co-Authors: Kondababu Kurakula, Mariska Vos, A. Logiantara, Joris J. T. H. Roelofs, Maartje A.e. Nieuwenhuis, Gerard H. Koppelman, Dirkje S. Postma, Leonie S. Van Rijt, Carlie J M De VriesAbstract: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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bone marrow specific deficiency of Nuclear Receptor Nur77 enhances atherosclerosis
Circulation Research, 2012Co-Authors: Anouk A J Hamers, Menno P J De Winther, Marion J J Gijbels, Vivian De Waard, Mariska Vos, Fadi Rassam, Kondababu Kurakula, Patrick J. Van Gorp, Goran Marinkovic, Carlie J M De VriesAbstract:Rationale: Nuclear Receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. Objective: This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow–specific deficiency of Nur77 on atherosclerosis. Methods and Results: We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77 −/− ) mice. Nur77 −/− BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77 −/− BMM cells. SDF-1α expression in nonstimulated Nur77 −/− BMM is repressed by Nur77 and the chemoattractive activity of Nur77 −/− BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77 −/− mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow–specific deficiency of Nur77 on atherosclerosis was studied in low density lipoprotein Receptor-deficient (Ldlr −/− ) mice. Ldlr −/− mice with a Nur77 −/− -deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow–transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77 −/− -transplanted mice, which may explain the observed aggravation of lesion formation. Conclusions: In conclusion, in bone marrow–derived cells the Nuclear Receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
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Bone Marrow–Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis
Circulation research, 2011Co-Authors: Anouk A J Hamers, Menno P J De Winther, Marion J J Gijbels, Vivian De Waard, Mariska Vos, Fadi Rassam, Goran Marinković, Kondababu Kurakula, Patrick J. Van Gorp, Carlie J M De VriesAbstract:Nuclear Receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis. We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77(-/-)) mice. Nur77(-/-) BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77(-/-) BMM cells. SDF-1α expression in nonstimulated Nur77(-/-) BMM is repressed by Nur77 and the chemoattractive activity of Nur77(-/-) BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77(-/-) mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow-specific deficiency of Nur77 on atherosclerosis was studied in low density lipoprotein Receptor-deficient (Ldlr(-/-)) mice. Ldlr(-/-) mice with a Nur77(-/-)-deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow-transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77(-/-)-transplanted mice, which may explain the observed aggravation of lesion formation. In conclusion, in bone marrow-derived cells the Nuclear Receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
