<br>SIRT6 通过调节血管内皮细胞中的 NRF2 抑制炎症反应,International Immunopharmacology

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SIRT6 通过调节血管内皮细胞中的 NRF2 抑制炎症反应
International Immunopharmacology ( IF 4.8 ) Pub Date : 2021-07-04 , DOI: 10.1016/j.intimp.2021.107926
Yanhao He ₁ , Guangde Yang ₂ , Lijing Sun ₃ , Hongqian Gao ₄ , Feng Yao ₂ , Zhen Jin ₄ , Zihan Zheng ₄ , Lifang Chen ₅ , Weirong Wang ₅ , Nanbo Zheng ₆ , Rong Lin ₄

Affiliation

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 sirtuin 家族 NAD+ 依赖性蛋白赖氨酸脱酰酶的成员，在调节新陈代谢、衰老和抗应激能力中起重要作用。然而，SIRT6 在血管炎症中的作用及其分子机制尚不清楚。本研究显示，TNF-α 在人脐静脉内皮细胞（HUVECs）中以浓度和时间依赖性方式显著降低 SIRT6 蛋白和 mRNA 的表达，并增加单核细胞趋化蛋白 1 （MCP-1）、白细胞介素（IL） -6 和 IL-1β 的表达。过表达 SIRT6 但不过表达其催化失活突变体抑制 TNF α诱导的 MCP-1 、 IL-6 和 IL-1β 的表达。敲低 SIRT6 显著增强 TNF α诱导的 MCP-1 、 IL-6 和 IL-1β 的表达。此外，敲低 SIRT6 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，而敲低 NRF2 显着增强了 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，敲低 SIRT6 降低了 NRF2 及其靶基因的表达。同时，敲低 SIRT6 抑制 NRF2 细胞核蛋白表达。此外，敲低 SIRT6 会降低 NRF2 的磷酸化，过表达 SIRT6 会增加 NRF2 的磷酸化。SIRT6 与 NRF2 相互作用。体内高脂血症小鼠血清中 TNF-α 和 IL-1β 水平升高。高脂血症诱导的 MCP-1 、 IL-6 和 IL-1β 的产生在内皮特异性 SIRT6 敲除小鼠中显著增加。相比之下，NRF2 及其靶基因的表达降低。综上所述，这些结果表明 SIRT6 通过其脱乙酰酶活性和 NRF2 依赖性信号通路来防止血管炎症。

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SIRT6 inhibits inflammatory response through regulation of NRF2 in vascular endothelial cells

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.

更新日期：2021-07-04

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