NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NF kappa B activation
Por:
Calvayrac, O, Rodriguez-Calvo, R, Marti-Pamies, I, Alonso, J, Ferran, B, Aguilo, S, Crespo, J, Rodriguez-Sinovas, A, Rodriguez, C, Martinez-Gonzalez, J
Publicada:
1 mar 2015
Resumen:
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-1 beta, IL-6 and IL-8) and chemokines (MCP-1 and CCL20). Similar effects were obtained in cells stimulated with TNF alpha 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 NF kappa B sensitive promoters (in transient transfections), and the binding of NF kappa B to its responsive element (in electrophoretic mobility shift assays). Furthermore, NOR-1 prevented the activation of NF kappa B pathway by decreasing I kappa B alpha 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 NF kappa B. In mouse challenged with LPS, the activation of the NF kappa B 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. (C) 2014 Elsevier Ltd. All rights reserved.
Filiaciones:
Calvayrac, O:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Rodriguez-Calvo, R:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Marti-Pamies, I:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Alonso, J:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Ferran, B:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Aguilo, S:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Crespo, J:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Rodriguez-Sinovas, A:
UAB, Univ Hosp, Barcelona, Spain
UAB, Inst Invest Vall dHebron, Barcelona, Spain
Rodriguez, C:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
Martinez-Gonzalez, J:
IIB St Pau, CSIC, ICCC, Ctr Invest Cardiovasc, Barcelona, Spain
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