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BMC Cardiovascular Disorders

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Open Access 01-12-2017 | Research article

Deletion of the NR4A nuclear receptor NOR1 in hematopoietic stem cells reduces inflammation but not abdominal aortic aneurysm formation

Authors: Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Published in: BMC Cardiovascular Disorders | Issue 1/2017

Abstract

Background

The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods

Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated fat to induce AAA formation. Quantification of AAA formation was performed by ultrasound and ex vivo measurements.

Results

Among 184 inflammatory genes that were analyzed, 36 genes were differentially regulated in LPS-treated NOR1-deficient macrophages. Albeit this difference in gene regulation, NOR1-deficiency in hematopoietic stem cells did not affect development of AAA formation in bone marrow-derived stem cell transplanted LDLr-deficient mice.

Conclusion

NOR1 deletion induced differential inflammatory gene transcription in macrophages but did not influence AAA formation in mice.

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Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for abdominal aortic aneurysm: a best-evidence systematic review for the U.S. preventive services task force. Ann Intern Med. 2005;142(3):203–11.CrossRefPubMed

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29–322.CrossRefPubMed

Koch AE, Haines GK, Rizzo RJ, Radosevich JA, Pope RM, Robinson PG, Pearce WH. Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response. Am J Pathol. 1990;137(5):1199–213.PubMedPubMedCentral

Saraff K, Babamusta F, Cassis LA, Daugherty A. Aortic dissection precedes formation of aneurysms and atherosclerosis in Angiotensin II-infused, Apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23(9):1621–6.CrossRefPubMed

Zhao Y, Bruemmer D. NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol. 2010;30(8):1535–41.CrossRefPubMedPubMedCentral

Hamers AA, Hanna RN, Nowyhed H, Hedrick CC, de Vries CJ. NR4A nuclear receptors in immunity and atherosclerosis. Curr Opin Lipidol. 2013;24(5):381–5.CrossRefPubMedPubMedCentral

Alonso J, Galan M, Marti-Pamies I, Romero JM, Camacho M, Rodriguez C, Martinez-Gonzalez J. NOR-1/NR4A3 regulates the cellular inhibitor of apoptosis 2 (cIAP2) in vascular cells: role in the survival response to hypoxic stress. Sci Rep. 2016;6:34056.CrossRefPubMedPubMedCentral

Mullican SE, Zhang S, Konopleva M, Ruvolo V, Andreeff M, Milbrandt J, Conneely OM. Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med. 2007;13(6):730–5.CrossRefPubMed

Qing H, Liu Y, Zhao Y, Aono J, Jones KL, Heywood EB, Howatt D, Binkley CM, Daugherty A, Liang Y, et al. Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis. Stem Cells. 2014;32(9):2419–29.CrossRefPubMedPubMedCentral

10.

Zhao Y, Howatt DA, Gizard F, Nomiyama T, Findeisen HM, Heywood EB, Jones KL, Conneely OM, Daugherty A, Bruemmer D. Deficiency of the NR4A orphan nuclear receptor NOR1 decreases monocyte adhesion and atherosclerosis. Circ Res. 2010;107(4):501–11.CrossRefPubMedPubMedCentral

11.

Pei L, Castrillo A, Tontonoz P. Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77. Mol Endocrinol. 2006;20(4):786–94.CrossRefPubMed

12.

Bonta PI, van Tiel CM, Vos M, Pols TW, van Thienen JV, Ferreira V, Arkenbout EK, Seppen J, Spek CA, van der Poll T, et al. Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses. Arterioscler Thromb Vasc Biol. 2006;26(10):2288–94.CrossRefPubMed

13.

Ipseiz N, Uderhardt S, Scholtysek C, Steffen M, Schabbauer G, Bozec A, Schett G, Kronke G. The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells. J Immunol. 2014;192(10):4852–8.CrossRefPubMed

14.

MacTaggart JN, Xiong W, Knispel R, Baxter BT. Deletion of CCR2 but not CCR5 or CXCR3 inhibits aortic aneurysm formation. Surgery. 2007;142(2):284–8.CrossRefPubMed

15.

Daugherty A, Rateri DL, Charo IF, Owens AP, Howatt DA, Cassis LA. Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE−/− mice. Clin Sci (Lond). 2010;118(11):681–9.CrossRef

16.

Findeisen HM, Gizard F, Zhao Y, Cohn D, Heywood EB, Jones KL, Lovett DH, Howatt DA, Daugherty A, Bruemmer D. Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol. 2011;31(2):253–60.CrossRefPubMed

17.

Nomiyama T, Zhao Y, Gizard F, Findeisen HM, Heywood EB, Jones KL, Conneely OM, Bruemmer D. Deficiency of the NR4A neuron-derived orphan receptor-1 attenuates neointima formation after vascular injury. Circulation. 2009;119(4):577–86.CrossRefPubMedPubMedCentral

18.

Kulkarni MM: Digital multiplexed gene expression analysis using the NanoString nCounter system. Curr Protoc Mol Biol 2011, Chapter 25:Unit25B.10.

19.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25(4):402–8.CrossRefPubMed

20.

Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000;105(11):1605–12.CrossRefPubMedPubMedCentral

21.

Krege JH, Hodgin JB, Hagaman JR, Smithies O. A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension. 1995;25(5):1111–5.CrossRefPubMed

22.

Bruemmer D, Daugherty A, Lu H, Rateri DL. Relevance of angiotensin II-induced aortic pathologies in mice to human aortic aneurysms. Ann N Y Acad Sci. 2011;1245:7–10.CrossRefPubMed

23.

Cassis LA, Gupte M, Thayer S, Zhang X, Charnigo R, Howatt DA, Rateri DL, Daugherty A. ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice. Am J Physiol Heart Circ Physiol. 2009;296(5):H1660–5.CrossRefPubMedPubMedCentral

24.

Lu H, Rateri DL, Bruemmer D, Cassis LA, Daugherty A. Novel mechanisms of abdominal aortic aneurysms. Curr Atheroscler Rep. 2012;14(5):402–12.CrossRefPubMedPubMedCentral

25.

Raffort J, Lareyre F, Clement M, Hassen-Khodja R, Chinetti G, Mallat Z. Monocytes and macrophages in abdominal aortic aneurysm. Nat Rev Cardiol. 2017;14(8):457–71.CrossRefPubMed

26.

Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045–51.CrossRefPubMedPubMedCentral

27.

De Paoli F, Eeckhoute J, Copin C, Vanhoutte J, Duhem C, Derudas B, Dubois-Chevalier J, Colin S, Zawadzki C, Jude B, et al. The neuron-derived orphan receptor 1 (NOR1) is induced upon human alternative macrophage polarization and stimulates the expression of markers of the M2 phenotype. Atherosclerosis. 2015;241(1):18–26.CrossRefPubMed

28.

Mellak S, Ait-Oufella H, Esposito B, Loyer X, Poirier M, Tedder TF, Tedgui A, Mallat Z, Potteaux S. Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe−/− mice. Arterioscler Thromb Vasc Biol. 2015;35(2):378–88.CrossRefPubMed

29.

Ju X, Ijaz T, Sun H, Ray S, Lejeune W, Lee C, Recinos A 3rd, Guo DC, Milewicz DM, Tilton RG, et al. Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17-interleukin 17 axis in C57BL/6 mice. Arterioscler Thromb Vasc Biol. 2013;33(7):1612–21.CrossRefPubMed

30.

Zhao Y, Howatt DA, Gizard F, Nomiyama T, Findeisen HM, Heywood EB, Jones KL, Conneely OM, Daugherty A, Bruemmer D. Deficiency of the NR4A orphan nuclear receptor NOR1 decreases Monocyte adhesion and atherosclerosis. Circ Res. 2010;107(4):501–11.CrossRefPubMedPubMedCentral

31.

Gopal K, Kumar K, Nandini R, Jahan P, Kumar MJ. High fat diet containing cholesterol induce aortic aneurysm through recruitment and proliferation of circulating agranulocytes in apoE knock out mice model. J Thromb Thrombolysis. 2010;30(2):154–63.CrossRefPubMed

Title: Deletion of the NR4A nuclear receptor NOR1 in hematopoietic stem cells reduces inflammation but not abdominal aortic aneurysm formation
Authors: Hua Qing
Karrie L. Jones
Elizabeth B. Heywood
Hong Lu
Alan Daugherty
Dennis Bruemmer
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Cardiovascular Disorders / Issue 1/2017
Electronic ISSN: 1471-2261
DOI: https://doi.org/10.1186/s12872-017-0701-4

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Conclusion

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