Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China; College of Life Sciences, Yantai University, Yantai, 264005, China.
School of Pharmacy, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
Int Immunopharmacol. 2021 Oct;99:107926. doi: 10.1016/j.intimp.2021.107926. Epub 2021 Jul 4.
Emerging evidence suggests that inflammation plays a pivotal role in Atherosclerosis. Sirtuin 6 (SIRT6), a member of NAD-dependent protein lysine deacylases of the sirtuin family, plays an important role in the regulation of metabolism, aging and stress resistance. However, the role of SIRT6 in vascular inflammation and its molecular mechanism is unknown. The present study showed that TNF-α significantly reduced the expression of SIRT6 protein and mRNA in a concentration- and time-dependent manner and increased the expression of monocyte chemotactic protein 1 (MCP-1), interleukin (IL) -6 and IL-1β in human umbilical vein endothelial cells (HUVECs). Overexpression of SIRT6 but not its catalytically inactive mutant inhibited TNF-α-induced expression of MCP-1, IL-6 and IL-1β. Knockdown of SIRT6 significantly enhanced TNF-α-induced expression of MCP-1, IL-6 and IL-1β. Moreover, knockdown of SIRT6 reduced TNF-α-induced nuclear factor erythroid 2 related factor 2 (NRF2) nucleus protein expression, whereas knockdown of NRF2 significantly enhanced TNF-α-induced expression of MCP-1, IL-6 and IL-1β. In addition, overexpression of SIRT6 increased NRF2 and its target genes expression, and knockdown of SIRT6 decreased NRF2 and its target genes expression. Meanwhile, knockdown of SIRT6 inhibited NRF2 nucleus protein expression. Further, knockdown of SIRT6 decreased phosphorylation of NRF2, overexpression of SIRT6 increased phosphorylation of NRF2. SIRT6 interacted with NRF2. In vivo, the levels of TNF-α and IL-1β were increased in the serum of hyperlipidemia mice. Hyperlipidemia-induced production of MCP-1, IL-6 and IL-1β was significantly augmented in the endothelium specific SIRT6 knockout mice. In contrast, the expression of NRF2 and its target genes was reduced. Taken together, these results indicate that SIRT6 protects against vascular inflammation via its deacetylase activity and the NRF2-dependent signaling pathway.
新出现的证据表明，炎症在动脉粥样硬化中起着关键作用。Sirtuin 6（SIRT6）是 NAD 依赖性蛋白赖氨酸去乙酰化酶家族的成员之一，在调节代谢、衰老和应激反应方面发挥着重要作用。然而，SIRT6 在血管炎症中的作用及其分子机制尚不清楚。本研究表明，TNF-α 以浓度和时间依赖的方式显著降低 SIRT6 蛋白和 mRNA 的表达，并增加人脐静脉内皮细胞（HUVECs）中单核细胞趋化蛋白 1（MCP-1）、白细胞介素（IL）-6 和 IL-1β 的表达。SIRT6 的过表达而非其无催化活性的突变体抑制了 TNF-α 诱导的 MCP-1、IL-6 和 IL-1β 的表达。SIRT6 的敲低显著增强了 TNF-α 诱导的 MCP-1、IL-6 和 IL-1β 的表达。此外，SIRT6 的敲低降低了 TNF-α 诱导的核因子红细胞 2 相关因子 2（NRF2）核蛋白表达，而 NRF2 的敲低显著增强了 TNF-α 诱导的 MCP-1、IL-6 和 IL-1β 的表达。此外，SIRT6 的过表达增加了 NRF2 及其靶基因的表达，而 SIRT6 的敲低降低了 NRF2 及其靶基因的表达。同时，SIRT6 的敲低抑制了 NRF2 核蛋白的表达。此外，SIRT6 的敲低降低了 NRF2 的磷酸化水平，而过表达 SIRT6 则增加了 NRF2 的磷酸化水平。SIRT6 与 NRF2 相互作用。在体内，高脂血症小鼠血清中 TNF-α 和 IL-1β 的水平升高。在内皮细胞特异性 SIRT6 敲除小鼠中，高脂血症诱导的 MCP-1、IL-6 和 IL-1β 的产生明显增强。相反，NRF2 及其靶基因的表达减少。综上所述，这些结果表明，SIRT6 通过其去乙酰化酶活性和 NRF2 依赖的信号通路来保护血管免受炎症的侵害。
