Research progress on orphan nuclear receptor NR4A1 in atherosclerosis

GAN Run; HUO Yan; HUANG Jinlu; YANG Quanjun; GUO Cheng

doi:10.3969/j.issn.1006-0111.2016.04.002

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2016 > 34(4): 292-296

GAN Run, HUO Yan, HUANG Jinlu, YANG Quanjun, GUO Cheng. Research progress on orphan nuclear receptor NR4A1 in atherosclerosis[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(4): 292-296. doi: 10.3969/j.issn.1006-0111.2016.04.002

Citation:

GAN Run, HUO Yan, HUANG Jinlu, YANG Quanjun, GUO Cheng. Research progress on orphan nuclear receptor NR4A1 in atherosclerosis[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(4): 292-296. doi: 10.3969/j.issn.1006-0111.2016.04.002

Research progress on orphan nuclear receptor NR4A1 in atherosclerosis

doi: 10.3969/j.issn.1006-0111.2016.04.002

1.
Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;Department of Pharmacy, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
2.
Department of Pharmacy, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China

Received Date: 2016-01-28
Rev Recd Date: 2016-04-22

Abstract

Orphan nuclear receptor NR4A1 from the NR4A subfamily is one of the transcriptional factors that have not identified specific ligands. Previous studies have found that NR4A1 could regulate cell proliferation, apoptosis, differentiation and stress responses by changing gene expression, post-translational modification and interactions between coregulatory proteins. Recently, it has shown that NR4A1 has an abnormal expression in human atherosclerotic lesions and has been identified as a key regulator gene in vascular cells dysfunction. Regulating NR4A1 expression can have an important impact on the proliferation of smooth muscle cell and endothelial cell activation,meanwhile it could reduce inflammation,foam cell formation and lipid deposition,inhibit vascular remodeling,and prevent the development of atherosclerosis. These studies suggest that NR4A1 might be a novel target for drug development in prevention and treatment of atherosclerosis.
- orphan nuclear receptor,
- NR4A1,
- atherosclerosis,
- vascular cells

References

[1]	Hollman DA, Milona A, van Erpecum KJ, et al. Anti-inflammatory and metabolic actions of FXR:insights into molecular mechanisms[J]. Biochim Biophys Acta, 2012, 1821(11):1443-1452.
[2]	Xiao X, Wang P, Chou KC. Recent progresses in identifying nuclear receptors and their families[J]. Curr Top Med Chem, 2013, 13(10):1192-1200.
[3]	聂鹏. NR4A孤儿核受体亚家族与动脉粥样硬化[J]. 心血管病学进展,2011,32(5):640-644.
[4]	Milbrandt J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene[J]. Neuron, 1988, 1(3):183-188.
[5]	Baker KD, Shewchuk LM, Kozlova T, et al. The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway[J]. Cell, 2003, 113(6):731-742.
[6]	Wang WJ, Wang Y, Chen HZ, et al. Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway[J]. Nat Chem Biol, 2014, 10(2):133-140.
[7]	Kurakula K, Koenis DS, van Tiel CM, et al. NR4A nuclear receptors are orphans but not lonesome[J]. Biochim Biophys Acta, 2014, 1843(11):2543-2555.
[8]	Libby P. History of discovery:inflammation in atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2012, 32(9):2045-2051.
[9]	de Vries CJM, van Achterberg TAE, Horrevoets AJG, et al. Differential display identification of 40 genes with altered expression in activated human smooth muscle cells:local expression in atherosclerotic lesions of smags, smooth muscle activation-specific genes[J]. J Biol Chem, 2000, 275(31):23939-23947.
[10]	Arkenbout EK, de Waard V, van Bragt M, et al. Protective function of transcription factor TR3 orphan receptor in atherogenesis:decreased lesion formation in carotid artery ligation model in TR3 transgenic mice[J]. Circulation, 2002, 106(12):1530-1535.
[11]	Pires NM, Pols TW, de Vries MR, et al. Activation of nuclear receptor Nur77 by 6-mercaptopurine protects against neointima formation[J]. Circulation, 2007, 115(4):493-500.
[12]	Bonta PI, Matlung HL, Vos M, et al. Nuclear receptor Nur77 inhibits vascular outward remodelling and reduces macrophage accumulation and matrix metalloproteinase levels[J]. Cardiovasc Res, 2010, 87(3):561-568.
[13]	Kim HJ, Kim JY, Lee SJ, et al. α-Lipoic acid prevents neointimal hyperplasia via induction of p38 mitogen-activated protein kinase/Nur77-mediated apoptosis of vascular smooth muscle cells and accelerates postinjury reendothelialization[J]. Arterioscler Thromb Vasc Biol, 2010, 30(11):2164-2172.
[14]	Cui M, Cai Z, Chu S, et al. Orphan nuclear receptor Nur77 inhibits angiotensin Ⅱ-induced vascular remodeling via downregulation of β-catenin[J]. Hypertension, 2016, 67(1):153-162.
[15]	Yu Y, Cai Z, Cui M, et al. The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice[J]. Int J Mol Med, 2015, 36(6):1547-1555.
[16]	Bonta PI, van Tiel CM, Vos M, et al. Nuclear orphan receptors Nur77, Nurr1 and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses[J]. Arterioscler Thromb Vasc Biol, 2006, 26(10):2288-2294.
[17]	Pei L, Castrillo A, Chen M, et al. Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli[J]. J Biol Chem, 2005, 280(32):29256-29262.
[18]	Pei L, Castrillo A, Tontonoz P. Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77[J]. Mol Endocrinol, 2006, 20(4):786-794.
[19]	Shao Q, Shen LH, Hu LH, et al. Nuclear receptor Nur77 suppresses inflammatory response dependent on COX-2 in macrophages induced by oxLDL[J]. J Mol Cell Cardiol, 2010, 49(2):304-311.
[20]	Hanna RN, Shaked I, Hubbeling HG, et al. NR4A1(Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis[J]. Circ Res, 2012, 110(3):416-427.
[21]	Hu YW, Zhang P, Yang JY, et al. Nur77 decreases atherosclerosis progression in apoE(-/-) mice fed a high-fat/high-cholesterol diet[J]. PLoS ONE, 2014, 9(1):e87313.
[22]	Gruber F, Hufnagl P, Hofer-Warbinek R, et al. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1(PAI-1) promoter regulates TNF alpha-induced PAI-1 expression[J]. Blood, 2003, 101(8):3042-3048.
[23]	You B, Jiang YY, Chen S, et al. The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of Ikappa Balpha expression[J]. Circ Res, 2009, 104(6):742-749.
[24]	Zeng H, Qin L, Zhao D, et al. Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity[J]. J Exp Med, 2006, 203(3):719-729.
[25]	Yang P, Wei X, Zhang J, et al. Antithrombotic effects of Nur77 and Nor1 are mediated through upregulating thrombomodulin expression in endothelial cells[J]. Arterioscler Thromb Vasc Biol, 2015, 36(2):361-369.
[26]	Qin Q, Chen M, Yi B, et al. Orphan nuclear receptor Nur77 is a novel negative regulator of endothelin-1 expression in vascular endothelial cells[J]. J Mol Cell Cardiol, 2014, 77:20-28.
[27]	Zhan Y, Du X, Chen H, et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77[J]. Nat Chem Biol, 2008, 4(9):548-556.
[28]	Huo Y, Yi B, Chen M, et al. Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation[J]. Biochem Pharmacol, 2014, 92(4):590-598.
[29]	Pekarsky Y, Hallas C, Palamarchuk A, et al. Akt phosphorylates and regulates the orphan nuclear receptor Nur77[J]. Proc Natl Acad Sci (USA), 2001, 98(7):3690-3694.
[30]	Lee SO, Li X, Hedrick E, et al. Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells[J]. Mol Endocrinol, 2014, 28(10):1729-1739.

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通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

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Research progress on orphan nuclear receptor NR4A1 in atherosclerosis

1. Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;Department of Pharmacy, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China

2. Department of Pharmacy, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China

Received Date: 2016-01-28

Rev Recd Date: 2016-04-22

Key words:

Abstract: Orphan nuclear receptor NR4A1 from the NR4A subfamily is one of the transcriptional factors that have not identified specific ligands. Previous studies have found that NR4A1 could regulate cell proliferation, apoptosis, differentiation and stress responses by changing gene expression, post-translational modification and interactions between coregulatory proteins. Recently, it has shown that NR4A1 has an abnormal expression in human atherosclerotic lesions and has been identified as a key regulator gene in vascular cells dysfunction. Regulating NR4A1 expression can have an important impact on the proliferation of smooth muscle cell and endothelial cell activation,meanwhile it could reduce inflammation,foam cell formation and lipid deposition,inhibit vascular remodeling,and prevent the development of atherosclerosis. These studies suggest that NR4A1 might be a novel target for drug development in prevention and treatment of atherosclerosis.

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Reference (30)

[1]	Hollman DA, Milona A, van Erpecum KJ, et al. Anti-inflammatory and metabolic actions of FXR:insights into molecular mechanisms[J]. Biochim Biophys Acta, 2012, 1821(11):1443-1452.
[2]	Xiao X, Wang P, Chou KC. Recent progresses in identifying nuclear receptors and their families[J]. Curr Top Med Chem, 2013, 13(10):1192-1200.
[3]	聂鹏. NR4A孤儿核受体亚家族与动脉粥样硬化[J]. 心血管病学进展,2011,32(5):640-644.
[4]	Milbrandt J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene[J]. Neuron, 1988, 1(3):183-188.
[5]	Baker KD, Shewchuk LM, Kozlova T, et al. The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway[J]. Cell, 2003, 113(6):731-742.
[6]	Wang WJ, Wang Y, Chen HZ, et al. Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway[J]. Nat Chem Biol, 2014, 10(2):133-140.
[7]	Kurakula K, Koenis DS, van Tiel CM, et al. NR4A nuclear receptors are orphans but not lonesome[J]. Biochim Biophys Acta, 2014, 1843(11):2543-2555.
[8]	Libby P. History of discovery:inflammation in atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2012, 32(9):2045-2051.
[9]	de Vries CJM, van Achterberg TAE, Horrevoets AJG, et al. Differential display identification of 40 genes with altered expression in activated human smooth muscle cells:local expression in atherosclerotic lesions of smags, smooth muscle activation-specific genes[J]. J Biol Chem, 2000, 275(31):23939-23947.
[10]	Arkenbout EK, de Waard V, van Bragt M, et al. Protective function of transcription factor TR3 orphan receptor in atherogenesis:decreased lesion formation in carotid artery ligation model in TR3 transgenic mice[J]. Circulation, 2002, 106(12):1530-1535.
[11]	Pires NM, Pols TW, de Vries MR, et al. Activation of nuclear receptor Nur77 by 6-mercaptopurine protects against neointima formation[J]. Circulation, 2007, 115(4):493-500.
[12]	Bonta PI, Matlung HL, Vos M, et al. Nuclear receptor Nur77 inhibits vascular outward remodelling and reduces macrophage accumulation and matrix metalloproteinase levels[J]. Cardiovasc Res, 2010, 87(3):561-568.
[13]	Kim HJ, Kim JY, Lee SJ, et al. α-Lipoic acid prevents neointimal hyperplasia via induction of p38 mitogen-activated protein kinase/Nur77-mediated apoptosis of vascular smooth muscle cells and accelerates postinjury reendothelialization[J]. Arterioscler Thromb Vasc Biol, 2010, 30(11):2164-2172.
[14]	Cui M, Cai Z, Chu S, et al. Orphan nuclear receptor Nur77 inhibits angiotensin Ⅱ-induced vascular remodeling via downregulation of β-catenin[J]. Hypertension, 2016, 67(1):153-162.
[15]	Yu Y, Cai Z, Cui M, et al. The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice[J]. Int J Mol Med, 2015, 36(6):1547-1555.
[16]	Bonta PI, van Tiel CM, Vos M, et al. Nuclear orphan receptors Nur77, Nurr1 and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses[J]. Arterioscler Thromb Vasc Biol, 2006, 26(10):2288-2294.
[17]	Pei L, Castrillo A, Chen M, et al. Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli[J]. J Biol Chem, 2005, 280(32):29256-29262.
[18]	Pei L, Castrillo A, Tontonoz P. Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77[J]. Mol Endocrinol, 2006, 20(4):786-794.
[19]	Shao Q, Shen LH, Hu LH, et al. Nuclear receptor Nur77 suppresses inflammatory response dependent on COX-2 in macrophages induced by oxLDL[J]. J Mol Cell Cardiol, 2010, 49(2):304-311.
[20]	Hanna RN, Shaked I, Hubbeling HG, et al. NR4A1(Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis[J]. Circ Res, 2012, 110(3):416-427.
[21]	Hu YW, Zhang P, Yang JY, et al. Nur77 decreases atherosclerosis progression in apoE(-/-) mice fed a high-fat/high-cholesterol diet[J]. PLoS ONE, 2014, 9(1):e87313.
[22]	Gruber F, Hufnagl P, Hofer-Warbinek R, et al. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1(PAI-1) promoter regulates TNF alpha-induced PAI-1 expression[J]. Blood, 2003, 101(8):3042-3048.
[23]	You B, Jiang YY, Chen S, et al. The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of Ikappa Balpha expression[J]. Circ Res, 2009, 104(6):742-749.
[24]	Zeng H, Qin L, Zhao D, et al. Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity[J]. J Exp Med, 2006, 203(3):719-729.
[25]	Yang P, Wei X, Zhang J, et al. Antithrombotic effects of Nur77 and Nor1 are mediated through upregulating thrombomodulin expression in endothelial cells[J]. Arterioscler Thromb Vasc Biol, 2015, 36(2):361-369.
[26]	Qin Q, Chen M, Yi B, et al. Orphan nuclear receptor Nur77 is a novel negative regulator of endothelin-1 expression in vascular endothelial cells[J]. J Mol Cell Cardiol, 2014, 77:20-28.
[27]	Zhan Y, Du X, Chen H, et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77[J]. Nat Chem Biol, 2008, 4(9):548-556.
[28]	Huo Y, Yi B, Chen M, et al. Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation[J]. Biochem Pharmacol, 2014, 92(4):590-598.
[29]	Pekarsky Y, Hallas C, Palamarchuk A, et al. Akt phosphorylates and regulates the orphan nuclear receptor Nur77[J]. Proc Natl Acad Sci (USA), 2001, 98(7):3690-3694.
[30]	Lee SO, Li X, Hedrick E, et al. Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells[J]. Mol Endocrinol, 2014, 28(10):1729-1739.

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Research progress on orphan nuclear receptor NR4A1 in atherosclerosis

doi: 10.3969/j.issn.1006-0111.2016.04.002

Abstract

References

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通讯作者: 陈斌, bchen63@163.com

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