Abstract

N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing angiogenesis and inflammation. A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-α. Here we show that A2E binds and transactivates also peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR). 9’-cis-norbixin, a di-apocarotenoid is also a ligand of these nuclear receptors (NR). Norbixin inhibits PPAR and RXR transactivation induced by A2E. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-κB and AP-1 transactivation and mRNA expression of the inflammatory interleukins (IL) -6 and -8 and of vascular endothelial growth factor (VEGF) enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression in response to A2E. Selective PPAR-α, -β/δ and –γ antagonists inhibit the expression of IL-6 and IL-8 while only the antagonist of PPAR-γ inhibits the transactivation of NF-κB following A2E exposure. In addition, a cocktail of all three PPARs antagonists and also HX531, an antagonist of RXR reproduce norbixin effects on inflammation. Altogether, A2E’s deleterious biological effects could be inhibited through PPAR and RXR regulation. Moreover, the modulation of these NR by norbixin may open new avenues for the treatment of AMD.

Highlights

  • age-related macular degeneration (AMD) is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older [1]

  • The level of transactivation of peroxisome proliferator-activated receptors (PPAR)-α, -β/δ, or -γ isoforms by A2E was determined by co-transfection of porcine retinal pigment epithelial cells (RPE) cells with a plasmid expressing each of the full-length PPAR isoforms and a plasmid expressing luciferase under the control of the PPAR response element

  • A2E increases the secretion of inflammatory cytokines [8, 9] and of vascular endothelial growth factor (VEGF) by RPE cells in vitro and in AMD animal models in vivo [10, 11]

Read more

Summary

Introduction

AMD is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older [1]. A2E itself increases the secretion of inflammatory cytokines by RPE cells in vitro and in AMD animal models in vivo [8, 9], and the expression of VEGF in vitro [10] and in vivo [11]. It has been proposed that A2E through induction of the transactivation of the α-isoform of the retinoic acid receptor (RAR) is responsible for VEGF production in vitro and in vivo [10, 11]. Www.aging-us.com pharmacological inhibition of RAR transactivation with the RAR- “specific” antagonist RO-41-5253 reduced A2E-induced VEGF production in vitro and in vivo [10, 11]. It has been shown that RO-41-5253 is a RAR antagonist, and a partial agonist of PPAR-γ [12] suggesting that PPARs might be involved in A2E’s effects

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call