RAR 抑制剂通过 PPAR 或 RXR 反式激活的非特异性调节，在体外 A2E 刺激的 RPE 细胞中显示光保护和抗炎作用,International Journal of Molecular Sciences

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RAR 抑制剂通过 PPAR 或 RXR 反式激活的非特异性调节，在体外 A2E 刺激的 RPE 细胞中显示光保护和抗炎作用
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2024-03-06 , DOI: 10.3390/ijms25053037
Valérie Fontaine ₁ , Thinhinane Boumedine ₁ , Elodie Monteiro ₁ , Mylène Fournié ₁ , Gersendre Gendre ₁ , José-Alain Sahel _{1,

2,

3} , Serge Picaud ₁ , Stanislas Veillet ₄ , René Lafont ₄ , Mathilde Latil ₄ , Pierre J. Dilda ₄ , Serge Camelo ₄

Affiliation

N-视黄基-N-视黄乙醇胺 (A2E) 通过诱导视网膜色素上皮 (RPE) 细胞死亡、血管生成和炎症而与年龄相关性黄斑变性 (AMD) 的病理生理学相关。此前人们认为 A2E 效应仅通过视黄酸受体 (RAR)-α 激活介导。然而，这一结论是基于使用 RAR“特异性”拮抗剂 RO-41-5253 进行的实验，该拮抗剂被发现也是过氧化物酶体增殖物激活受体 (PPAR)-γ 的配体和部分激动剂。此外，我们之前报道过，用降红木素抑制 PPAR 和类视黄醇 X 受体 (RXR) 反式激活也可以调节 A2E 存在下的 RPE 细胞的炎症和血管生成。在这里，我们使用几种 RAR 抑制剂，破译了 RAR、PPAR 和 RXR 反式激活在 AMD 体外模型中各自的作用。我们发现，BMS 195614（一种选择性 RAR-α 拮抗剂）在 A2E 存在的情况下表现出针对有毒蓝光暴露的光保护特性。BMS 195614 还显着降低体外 RPE 细胞中 A2E 诱导的 AP-1 反式激活以及炎症白细胞介素 (IL)-6 和血管内皮生长因子 (VEGF) 的 mRNA 表达，表明 RAR 在这些过程中发挥着重要作用。然而，令人惊讶的是，我们发现 (1) Norbixin 增加了 RAR 反式激活，(2) AGN 193109（一种高亲和力泛 RAR 拮抗剂）和 BMS 493（一种泛 RAR 反向激动剂），它们对有毒蓝光照射具有光保护作用在 A2E 存在的情况下，还分别抑制 PPAR 反式激活和 RXR 反式激活。因此，在我们的AMD体外模型中，几种商业化的RAR抑制剂似乎是非特异性的，我们认为A2E在RPE细胞中诱导的光毒性和IL-6和VEGF的表达是通过激活PPAR或RXR来发挥作用的，而不是通过激活PPAR或RXR来发挥作用。与 RAR 反式激活相比。

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RAR Inhibitors Display Photo-Protective and Anti-Inflammatory Effects in A2E Stimulated RPE Cells In Vitro through Non-Specific Modulation of PPAR or RXR Transactivation

N-retinylidene-N-retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and inflammation in retinal pigmented epithelial (RPE) cells. It was previously thought that the A2E effects were solely mediated via the retinoic acid receptor (RAR)-α activation. However, this conclusion was based on experiments using the RAR “specific” antagonist RO-41-5253, which was found to also be a ligand and partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. Moreover, we previously reported that inhibiting PPAR and retinoid X receptor (RXR) transactivation with norbixin also modulated inflammation and angiogenesis in RPE cells challenged in the presence of A2E. Here, using several RAR inhibitors, we deciphered the respective roles of RAR, PPAR and RXR transactivations in an in vitro model of AMD. We showed that BMS 195614 (a selective RAR-α antagonist) displayed photoprotective properties against toxic blue light exposure in the presence of A2E. BMS 195614 also significantly reduced the AP-1 transactivation and mRNA expression of the inflammatory interleukin (IL)-6 and vascular endothelial growth factor (VEGF) induced by A2E in RPE cells in vitro, suggesting a major role of RAR in these processes. Surprisingly, however, we showed that (1) Norbixin increased the RAR transactivation and (2) AGN 193109 (a high affinity pan-RAR antagonist) and BMS 493 (a pan-RAR inverse agonist), which are photoprotective against toxic blue light exposure in the presence of A2E, also inhibited PPARs transactivation and RXR transactivation, respectively. Therefore, in our in vitro model of AMD, several commercialized RAR inhibitors appear to be non-specific, and we propose that the phototoxicity and expression of IL-6 and VEGF induced by A2E in RPE cells operates through the activation of PPAR or RXR rather than by RAR transactivation.

更新日期：2024-03-07

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