SIRT6 inhibits TNF-α-induced inflammation of vascular adventitial fibroblasts through ROS and Akt signaling pathway
SIRT6 inhibits TNF-α-induced inflammation of vascular adventitial fibroblasts through ROS and Akt signaling pathway
复制标题
SIRT6通过ROS和Akt信号通路抑制TNF-α诱导的血管外膜成纤维细胞炎症
DOI：
10.1016/j.yexcr.2017.05.001
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发表时间：
2017-08-01
影响因子：
3.7
通讯作者：
Lin, Rong
中科院分区：
文献类型：
--
作者：
He, Yanhao;Xiao, Yunfang;Lin, Rong
SIRT6 具有脱乙酰酶和 ADP-核糖基转移酶活性，主要在细胞核中表达。研究表明SIRT6调节新陈代谢、衰老和抗应激等多种生物学功能。本研究旨在探讨SIRT6在血管炎症中的作用及其分子机制。我们发现肿瘤坏死因子-α (TNF-α) 不会改变 SIRT6 在血管外膜成纤维细胞 (VAF)、血管内皮细胞 (VEC) 和血管平滑肌细胞 (VSMC) 中的定位。 TNF-α处理的VAF中SIRT1、SIRT6的表达降低。相反，TNF-α显着增加单核细胞趋化蛋白1（MCP-1）和白细胞介素（IL）-6的表达。 siRNA 敲低 SIRT1 和 SIRT6 分别显着增强 TNF-α 诱导的 MCP-1 和 IL-6 表达。 SIRT1 和 SIRT6 的过表达抑制了 TNF-α 诱导的 VAF 中 MCP-1 和 IL-6 的表达。此外，我们还发现SIRT1正向调节VAF中SIRT6的表达。此外，敲低 SIRT1 和 SIRT6 分别增强了 TNF-α 诱导的活性氧 (ROS) 的产生和蛋白激酶 B (Akt) 的磷酸化。 ROS 清除剂 N-乙酰基-L-半胱氨酸 (NAC) 和 Akt 抑制剂 MK2206 降低了 VAF 中 TNF-α 诱导的 MCP-1 和 IL-6 mRNA 表达。体内研究表明，颈动脉环诱发的血管炎症中SIRT1、SIRT6的表达降低，MCP-1、IL-6和IL-1β的表达增加。综上所述，这些发现表明 SIRT1 和 SIRT6 通过 ROS 和 Akt 途径抑制 TNF-α 诱导的 VAF 炎症。
SIRT6, with both deacetylase and ADP-ribosyltransferase activities, is predominantly expressed in the nucleus. It has been revealed that SIRT6 regulates various biological functions including metabolism, aging and stress resistance. This study aims to investigate the role of SIRT6 in vascular inflammation and it molecular mechanism. We found that tumor necrosis factor-alpha (TNF-alpha) did not alter the localization of SIRT6 in vascular adventitial fibroblasts (VAFs), vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). The expression of SIRT1, SIRT6 was decreased in TNF-alpha-treated VAFs. In contrast, TNF-alpha significantly increased the expression of monocyte chemotactic protein 1 (MCP-1) and interleukin (IL) -6. Knockdown of SIRT1 and SIRT6 by siRNA significantly enhanced TNF-alpha-induced expression of MCP-1 and IL-6, respectively. Overexpression of SIRT1 and SIRT6 inhibited TNF-alpha-induced expression of MCP-1 and IL-6 in VAFs. Moreover, we also found SIRT1 positively regulated the expression of SIRT6 in VAFs. In addition, knockdown of SIRT1 and SIRT6 respectively augmented TNF-alpha-induced generation of reactive oxygen species (ROS) and phosphorylation of protein kinase B (Akt). ROS scavenger N-acetyl-L-cysteine (NAC) and Akt inhibitor MK2206 reduced TNF-alpha-induced mRNA expression of MCP-1 and IL-6 in VAFs. In vivo studies indicated that the expression of SIRT1, SIRT6 was decreased and the expression of MCP-1, IL-6 and IL-1 beta was increased in carotid collar-induced vascular inflammation. Taken together, these findings indicate that SIRT1 and SIRT6 inhibit TNF-alpha-induced inflammation in VAFs by ROS and Akt pathway.