NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation. (March 2015)

• Record Type: Journal Article
• Authors: Calvayrac, Olivier; Rodríguez-Calvo, Ricardo; Martí-Pamies, Ingrid; Alonso, Judith; Ferrán, Beatriz; Aguiló, Silvia; Crespo, Javier; Rodríguez-Sinovas, Antonio; Rodríguez, Cristina; Martínez-González, José
• Is Part Of: Journal of molecular and cellular cardiology. Volume 80(2015:Mar.)
• Page Start: 34
• Page End: 44
• Publication Date: 2015-03
• Subjects: DMEM Dulbecco's modified Eagle's medium -- EC endothelial cells -- EGFP Enhanced Green Fluorescent Protein -- EMSA electrophoretic mobility shift assay -- FCS foetal calf serum -- hNOR1 human NOR-1 -- MDA malondialdehyde -- MOI multiplicity of infection -- nLDL native low-density lipoproteins -- NR4A nuclear receptor 4A -- oxLDL oxidized LDL -- siRNA small interfering RNA -- TBARS thiobarbituric acid-reactive substances -- TgNOR-1 transgenic mouse for NOR-1 -- VSMCs vascular smooth muscle cells -- WT wild-type; Vascular smooth muscle cells -- Cytokine -- Gene expression -- Inflammation -- NOR-1; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2014.12.015
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Recent work has highlighted the role of NR4A receptors in atherosclerosis and inflammation. In vascular smooth muscle cell (VSMC) proliferation, however, NOR-1 (neuron-derived orphan receptor-1) exerts antagonistic effects to Nur77 and Nurr1. The aim of this study was to analyse the effect of NOR-1 in VSMC inflammatory response. We assessed the consequence of a gain-of-function of this receptor on the response of VSMC to inflammatory stimuli. In human VSMC, lentiviral over-expression of NOR-1 reduced lipopolysaccharide (LPS)-induced up-regulation of cytokines (IL-1β, IL-6 and IL-8) and chemokines (MCP-1 and CCL20). Similar effects were obtained in cells stimulated with TNFα or oxLDL. Conversely, siRNA-mediated NOR-1 inhibition significantly increased the expression of pro-inflammatory mediators. Interestingly, in the aortas from transgenic mice that over-express human NOR-1 in VSMC (TgNOR-1), the up-regulation of cytokine/chemokine by LPS was lower compared to wild-type littermates. Similar results were obtained in VSMC from transgenic animals. NOR-1 reduced the transcriptional activity of NFκB sensitive promoters (in transient transfections), and the binding of NFκB to its responsive element (in electrophoretic mobility shift assays). Furthermore, NOR-1 prevented the activation of NFκB pathway by decreasing IκBα phosphorylation/degradation and inhibiting the phosphorylation and subsequent translocation of p65 to the nucleus (assessed by Western blot and immunocytochemistry). These effects were associated with an attenuated phosphorylation of ERK1/2, p38 MAPK and Jun N-terminal kinase, pathways involved in the activation of NFκB. In mouse challenged with LPS, the activation of the NFκB signalling was also attenuated in the aorta from TgNOR-1. Our data support a role for NOR-1 as a negative modulator of the acute response elicited by pro-inflammatory stimuli in the vasculature. Highlights: NOR-1 limits the inflammatory response of human VSMC induced by inflammatory stimuli. NOR-1 modulates VSMC inflammatory response by interfering with NFκB signalling. This effect was confirmed in a transgenic mouse that over-expresses NOR-1 in VSMC.