Efectos de los ligandos de receptores LXR sobre la activación de macrófagos y el desarrollo de aneurismas aórticos abdominales

• Autores: Paloma Guillem Llobat
• Directores de la Tesis: Miguel Ángel Íñiguez Peña (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2013
• Idioma: español
• Tribunal Calificador de la Tesis: Manuel Fresno Escudero (presid.), Miguel Campanero Garcia (secret.), Juan Miguel Redondo Moya (voc.), Lisardo Boscá (voc.), Mercedes Salaices Sánchez (voc.)
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Liver X receptors (LXRs) are nuclear receptors that act as ligand-dependent transcription factors and form permissive heterodimers with other nuclear receptors named retinoid X receptors (RXR). Once they are activated by either LXR ligands or RXR ligands, these nuclear receptors can integrate both lipid metabolism and inflammatory processes by regulating the expression of genes that are implicated in these signaling pathways. In this study we show that macrophage cell lines and also primary macrophages express functional LXR¿ and LXRß isoforms. We report an inhibitory effect on the LPS-induced expression of cyclooxygenase-2 (COX-2) upon treatment of macrophages with LXR ligands, either naturally-occurring, such as oxysterols, or synthetic, as GW3965 and TO901317. Downregulation of COX-2 expression is enhanced when cells are incubated with a combination of LXR plus RXR ligands. A similar inhibitory effect by these ligands was observed when analyzing the LPS-induced expression of microsomal prostaglandin E2 synthase-1 (mPGES-1). Consequently, there was a reduction in PGE2 production in cells treated with LXR ligands prior to LPS stimulation. The study of the inhibitory effects of LXRs on LPS-induced expression of COX-2 and mPGES-1 has led us to determine the existence of a transcriptional interference mechanism through the modulation of the activity of transcription factors such as NF¿B, but also Egr-1, which had not been previously associated with LXR-mediated gene repression. On the other hand, macrophages incubated with RXR or RAR (retinoid receptors) ligands, displayed an increased expression of cyclooxygenase-1 (COX-1) both at mRNA and protein levels. Induction of COX-1 via RXR/RAR is dependent on de novo protein synthesis, thus suggesting an indirect effect of RXR/RAR activation.

    Moreover, our results show a reduction in RAW264.7 macrophages migration in response to different stimuli after LXR activation, an effect that could contribute to the anti-inflammatory actions ascribed to these nuclear receptors.

    The present work has also sought to provide new insights into the effects of LXR activation in vivo in a model of abdominal aortic aneurysm (AAA) using ApoE-/- mice infused with angiotensin II (Ang.II) and treated with the LXR synthetic ligand TO901317. The results obtained showed a decrease in the development and severity of aortic lesions with lower expression of some pro-inflammatory genes, as well as the CD68 macrophage surface marker, in the Ang.II group treated with TO901317 in comparison with mice infused with AngII and treated with vehicle. Therefore, these data open a new field for the study of LXRs ligands as potential therapeutic agents in the control of the development and progression of abdominal aortic aneurisms.