The protective effect of hydroxytyrosol acetate against inflammation of vascular endothelial cells partly through the SIRT6-mediated PKM2 signaling pathway
The protective effect of hydroxytyrosol acetate against inflammation of vascular endothelial cells partly through the SIRT6-mediated PKM2 signaling pathway
复制标题
羟基酪醇乙酸酯部分通过SIRT6介导的PKM2信号通路对血管内皮细胞炎症的保护作用
DOI：
10.1039/c9fo00586b
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发表时间：
2019-09-01
期刊：
影响因子：
6.1
通讯作者：
Lin, Rong
中科院分区：
文献类型：
--
作者：
Yao, Feng;Yang, Guangde;Lin, Rong
羟基酪醇乙酸酯（HT-AC）是橄榄油中的一种多酚化合物，对小鼠胶原诱导的关节炎具有抗炎作用。然而，HT-AC对心血管疾病炎症反应的影响尚不清楚。因此，本研究旨在探讨HT-AC对血管内皮细胞炎症反应的影响及其分子机制。我们的研究结果表明，HT-AC抑制高胆固醇血症小鼠和肿瘤坏死因子（TNF）刺激的HUVECs的炎症反应。同时，HT-AC还上调SIRT 6在高胆固醇血症小鼠和HUVECs中的表达。为了进一步研究SIRT 6是否参与HT-AC对内皮炎症反应的调节，使用内皮特异性Sirt 6敲除（Sirt 6（endo-/-））小鼠。我们的研究发现，Sirt 6（endo-/-）取消了HT-AC对高胆固醇血症小鼠胸主动脉炎症反应的抑制作用。体外研究还表明，SIRT 6的敲低降低了HT-AC对炎症反应的抑制，而SIRT 6的过表达增强了HT-AC对HUVECs炎症反应的抑制。进一步的研究表明HT-AC的抗炎作用部分是通过SIRT 6介导的PKM 2信号通路实现的。此外，HT-AC通过TNF受体超家族成员1A（TNFRSF 1A）信号通路抑制TNF诱导的炎症反应。这些结果表明，HT-AC调节血管内皮炎症反应部分通过TNFRSF 1A/SIRT 6/PKM 2介导的信号通路。
Hydroxytyrosol acetate (HT-AC), a polyphenolic compound in olive oil, exerts an anti-inflammatory effect on murine collagen-induced arthritis. However, the effect of HT-AC on inflammatory response in cardiovascular disease remains unclear. Thus, in this study, we aimed to investigate the effect of HT-AC on the inflammation response of vascular endothelial cells and the related molecular mechanism. Our results showed that HT-AC inhibited the inflammatory response in hypercholesterolemic mice and tumor necrosis factor (TNF)-stimulated HUVECs. Meanwhile, HT-AC also up-regulated SIRT6 expression in hypercholesterolemic mice and HUVECs. To further investigate whether SIRT6 is involved in the regulation of endothelial inflammatory response by HT-AC, endothelium-specific Sirt6 knockout (Sirt6(endo-/-)) mice were used. Our study found that Sirt6(endo-/-) abolished the inhibition of inflammatory response by HT-AC in the thoracic aorta of hypercholesterolemic mice. In vitro study also showed that knockdown of SIRT6 reduced the inhibition of inflammatory response by HT-AC, whereas overexpression of SIRT6 augmented the inhibition of inflammatory response by HT-AC in HUVECs. Further study demonstrated that HT-AC exerts its anti-inflammatory effect partly via the SIRT6-mediated PKM2 signaling pathway. In addition, HT-AC inhibited TNF-induced inflammatory response through the TNF receptor superfamily member 1A (TNFRSF1A) signaling pathway. These findings indicate that HT-AC regulates the vascular endothelial inflammatory response partly through the TNFRSF1A/SIRT6/PKM2-mediated signaling pathway.