Published online before print July 27, 2006, doi: 10.1161/01.ATV.0000238346.84458.5d
© 2006 American Heart Association, Inc.
Vascular Biology |
Nuclear Receptors Nur77, Nurr1, and NOR-1 Expressed in Atherosclerotic Lesion Macrophages Reduce Lipid Loading and Inflammatory Responses
From the Departments of Medical Biochemistry (P.I.B., C.M.v.T., M.V., J.V.v.T., V.F., E.K.A., H.P., C.J.M.d.V.), Experimental Internal Medicine (C.A.S., T.v.d.P.), and the AMC Liver Center (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
Correspondence to Dr. Carlie J. de Vries, Department of Medical Biochemistry K1–116, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. E-mail C.J.deVries{at}amc.uva.nl
Objective— Atherosclerosis is an inflammatory disease in which macrophage activation and lipid loading play a crucial role. In this study, we investigated expression and function of the NR4A nuclear receptor family, comprising Nur77 (NR4A1, TR3), Nurr1 (NR4A2), and NOR-1 (NR4A3) in human macrophages.
Methods and Results— Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry. Protein expression localizes to the nucleus. Primary and THP-1 macrophages transiently express NR4A-factors in response to lipopolysaccharide and tumor necrosis factor 
. Lentiviral overexpression of Nur77, Nurr1, or NOR-1 reduces expression and production of interleukin (IL)-1ß and IL-6 proinflammatory cytokines and IL-8, macrophage inflammatory protein-1 and -1ß and monocyte chemoattractant protein-1 chemokines. In addition, NR4A-factors reduce oxidized–low-density lipoprotein uptake, consistent with downregulation of scavenger receptor-A, CD36, and CD11b macrophage marker genes. Knockdown of Nur77 or NOR-1 with gene-specific lentiviral short-hairpin RNAs resulted in enhanced cytokine and chemokine synthesis, increased lipid loading, and augmented CD11b expression, demonstrating endogenous NR4A-factors to inhibit macrophage activation, foam-cell formation, and differentiation.
Conclusion— NR4A-factors are expressed in human atherosclerotic lesion macrophages and reduce human macrophage lipid loading and inflammatory responses, providing further evidence for a protective role of NR4A-factors in atherogenesis.
We demonstrate that the NR4A family of transcription factors, comprising Nur77, Nurr1, and NOR-1, is expressed in human atherosclerotic lesion macrophages and reduces inflammatory responses and lipid loading involving inhibition of macrophage differentiation. Consequently, these receptors reduce foam-cell formation and may prevent lesion macrophages from producing excessive chemokines and cytokines.
Key Words: atherosclerosis • foam-cell formation • inflammation • macrophage function • nuclear orphan receptors • NR4A
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