Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Liu, Yan; Zhang, Jian; Yi, Bing; Chen, Ming; Jia, Qi; Yin, Yongguang; Lu, Xianghua; Jasmin, Jean-François; Sun, Jianxin

doi:10.1165/rcmb.2013-0198oc

Cited by 32 publications

(31 citation statements)

References 48 publications

(59 reference statements)

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“…[8][9][10] In VSMCs, Nur77 can be induced by multiple stimuli, including cytokines, growth factors, oxidized low-density lipoprotein, and vascular injury. 11,25,26 We found that Nur77 was highly expressed in medial VSMCs of thoracic aortas from Ang II-infused mice in vivo and in cultured VSMCs after Ang II stimulation in vitro. Several signaling pathways and transcription factors, including MAPK and nuclear factor-κB signaling pathways and MEF-2, AP-1, and CREB, have been reported to regulate the expression of Nur77 in various cell types.…”

Section: Discussionmentioning

confidence: 85%

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

et al. 2016

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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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Section: Discussionmentioning

confidence: 85%

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

et al. 2016

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“…However, Nur77-deficient mice do not show any obvious T cell phenotype (16). A recent study showed that Nur77 inhibits airway smooth muscle cell proliferation in vitro, but this study lacks in vivo data (28). To assess whether Nur77 similarly as in the vessel wall inhibits airway smooth muscle cell proliferation, chronic allergic experiments need to be performed.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, peripheral eosinophils from patients with atopic dermatitis show increased Nur77 expression (26). Limited information is available on Nur77 in the lung, but its expression has been described in lung epithelial cells, and a recent study demonstrated that Nur77 inhibits pulmonary smooth muscle cell proliferation (27,28).…”

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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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“…Knockdown of Nur77 expression was performed by using Nur77 siRNAs, with AllStars negative siRNAs (QIAGEN, Valencia, CA) as a control, as described previously [28]. 2 hrs after seeded into the 6 well plates, cells were transfected using HiPerFect Transfection Reagent (QIAGEN, Valencia, CA) according to the manufacture's protocol.…”

Section: Methodsmentioning

confidence: 99%

Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation

Huo

Chen

et al. 2014

Biochemical Pharmacology

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Nur77 is an orphan nuclear receptor that belongs to the nuclear receptor 4A (NR4A) subfamily, which has been implicated in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 has recently been shown to be beneficial for the treatment of cardiovascular and metabolic diseases. The purpose of this study is to identify novel natural Nur77 activators and investigate their roles in preventing vascular diseases. By measuring Nur77 expression using quantitative RT-PCR, we screened active ingredients extracted from Chinese herb medicines with beneficial cardiovascular effects. Hyperoside (quercetin 3-D-galactoside) was identified as one of the potent activators for inducing Nur77 expression and activating its transcriptional activity in vascular smooth muscle cells (VSMCs). We demonstrated that hyperoside, in a time and dose dependent manner, markedly increased the expression of Nur77 in rat VSMCs, with an EC50 of ∼0.83μM. Mechanistically, we found that hyperoside significantly increased the phosphorylation of ERK1/2 MAP kinase and its downstream target cAMP response element-binding protein (CREB), both of which contributed to the hyperoside-induced Nur77 expression in rat VSMCs. Moreover, through activation of Nur77 receptor, hyperoside markedly inhibited both vascular smooth muscle cell proliferation in vitro and the carotid artery ligation–induced neointimal formation in vivo. These findings demonstrate that hyperoside is a potent natural activator of Nur77 receptor, which can be potentially used for prevention and treatment of occlusive vascular diseases.

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Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Cited by 32 publications

References 48 publications

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

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

Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation

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