title: NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation.
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.
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Olivier
authors.initials: O
authors.lastname: Calvayrac
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Martí-Pamies
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Alonso
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ferrán
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Aguiló
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Crespo
authors.affiliation: Hospital Universitario e Institut de Investigación del Vall d'Hebron, UAB, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodríguez-Sinovas
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain. Electronic address: crodriguezs@csic-iccc.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain. Electronic address: jmartinez@csic-iccc.org.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D026901:Membrane Transport Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; C479458:OSCP1 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone
keywords: Cytokine; Gene expression; Inflammation; NOR-1; Vascular smooth muscle cells