NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation

• Published in: Journal of molecular and cellular cardiology 2015-03, Vol.80, p.34-44
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Cardiovascular; Cells, Cultured; Cytokine; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression; Gene Expression Regulation; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation Mediators - metabolism; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Mice, Transgenic; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NF-kappa B - metabolism; NOR-1; Protein Binding; Receptors, Steroid - genetics; Receptors, Steroid - metabolism; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - metabolism; Signal Transduction; Transcriptional Activation; Vascular smooth muscle cells
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2014.12.015

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.