Department of Life Sciences, University of Siena, Siena, Italy.
Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
Eur J Nutr. 2020 Mar;59(2):517-527. doi: 10.1007/s00394-019-01920-x. Epub 2019 Feb 6.
Endothelial-to-mesenchymal transition (EndMT) plays an important role in pathogenesis of a number of inflammatory diseases. Hydroxytyrosol (HT) and, particularly, its major plasma metabolite HT-3O sulfate (HT-3Os) are known olive oil antioxidant and anti-inflammatory polyphenols which exert benefits against vascular diseases by improving endothelial function. However, to date the HT-3Os role in EndMT is not well known.
To investigate the HT-3Os effects on EndMT in the inflamed endothelium, we used an in vitro model of endothelial dysfunction, challenging endothelial cells (EC), human umbilical EC (HUVEC) and human retinal EC (HREC) with Interleukin-1β (IL-1β), an inflammatory agent. HREC were used as a specific model to investigate HT-3Os effects on vascular retinal diseases.
We found that IL-1β treatment-induced EndMT phenotype in both cell models, also changing cell morphology. HT-3Os protected EC against IL-1β effects, recovering cell morphology and phenotype. Mechanistically, HT-3Os targeting fibroblast growth factor receptor 1 FGFR1 expression and let-7 miRNA, controlled transforming growth factor beta (TGF-β) signalling in EC, downregulating transcription factors expression (SNAI1 and ZEB2) and gene expression of late EndMT markers (FN1, VIM, NOTCH3, CNN1, MMP2 and MMP9).
These results demonstrate that HT-3Os blunts pathological EndMT in inflamed EC, maintaining high let-7 miRNA expression and preventing activation of TGF-β signalling.
内皮-间充质转化（EndMT）在许多炎症性疾病的发病机制中起着重要作用。羟基酪醇（HT），特别是其主要的血浆代谢物 HT-3O 硫酸盐（HT-3Os），是已知的橄榄油抗氧化和抗炎多酚，通过改善内皮功能对血管疾病有益。然而，迄今为止，HT-3Os 在 EndMT 中的作用尚不清楚。
为了研究 HT-3Os 对炎症内皮中 EndMT 的影响，我们使用了内皮功能障碍的体外模型，用白细胞介素-1β（IL-1β），一种炎症剂，挑战内皮细胞（EC），人脐静脉内皮细胞（HUVEC）和人视网膜内皮细胞（HREC）。HREC 被用作研究 HT-3Os 对血管性视网膜疾病影响的特定模型。
我们发现，IL-1β 处理诱导了两种细胞模型中的 EndMT 表型，也改变了细胞形态。HT-3Os 保护 EC 免受 IL-1β 的影响，恢复了细胞形态和表型。从机制上讲，HT-3Os 靶向成纤维细胞生长因子受体 1（FGFR1）的表达和 let-7 miRNA，控制 EC 中的转化生长因子-β（TGF-β）信号，下调转录因子表达（SNAI1 和 ZEB2）和晚期 EndMT 标志物（FN1、VIM、NOTCH3、CNN1、MMP2 和 MMP9）的基因表达。
这些结果表明，HT-3Os 可阻止炎症 EC 中的病理性 EndMT，维持高 let-7 miRNA 表达，并防止 TGF-β 信号的激活。
