Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China.
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Department of Pharmacy, Xi'an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, PR China.
Int Immunopharmacol. 2022 Sep;110:109056. doi: 10.1016/j.intimp.2022.109056. Epub 2022 Jul 21.
Our previous study showed that Sirtuin 6 (Sirt6) plays an important role in the regulation of vascular endothelial cell inflammation. Recently, studies have reported that the RNA binding protein Lin28b directly regulates the let-7 microRNA (miRNA), which participates in the process of atherosclerosis (AS) by regulating inflammation. Pyroptosis is a form of programmed cell death that is accompanied by inflammation and is critical for AS. Thus, this study aimed to investigate the role of Sirt6 and Lin28b in vascular endothelial cell pyroptosis and the related mechanism. The present study showed that Lin28b expression was upregulated in the aortic intima and aorta of apolipoprotein E knockout (ApoE) mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found Lin28b was involved in tumor necrosis factor-α (TNF-α)-induced vascular endothelial cell pyroptosis, as indicated by the increased number of PI-positive cells and gasdermin D (GSDMD) cleavage, as well as the increased release of lactate dehydrogenase (LDH) and interleukin (IL)-1β. Further studies demonstrated that TNF-α significantly decreased the expression of let-7, while Lin28b knockdown significantly increased the expression of let-7a, let-7d and let-7g. In addition, Sirt6 overexpression decreased Lin28b expression. Moreover, Sirt6 overexpression suppressed pyroptosis by decreasing the number of PI-positive cells and GSDMD cleavage, as well as by decreasing the release of LDH and IL-1β in TNF-α-induced vascular endothelial cells. Further mechanistic studies revealed that Sirt6 directly interacted with and deacetylated Lin28b. Taken together, these findings indicate that Sirt6 inhibits vascular endothelial cell pyroptosis by negatively regulating the Lin28b/let-7 pathway in AS.
我们之前的研究表明，Sirtuin 6（Sirt6）在血管内皮细胞炎症的调节中发挥重要作用。最近的研究报道，RNA 结合蛋白 Lin28b 可直接调节 let-7 微 RNA（miRNA），通过调节炎症参与动脉粥样硬化（AS）的发生。细胞焦亡是一种伴随炎症的程序性细胞死亡形式，对 AS 至关重要。因此，本研究旨在探讨 Sirt6 和 Lin28b 在血管内皮细胞焦亡中的作用及其相关机制。本研究表明，高脂饮食喂养 8 或 12 周的载脂蛋白 E 基因敲除（ApoE）小鼠主动脉内膜和主动脉中 Lin28b 表达上调。然后，体外研究发现 Lin28b 参与肿瘤坏死因子-α（TNF-α）诱导的血管内皮细胞焦亡，PI 阳性细胞和 Gasdermin D（GSDMD）裂解增多，乳酸脱氢酶（LDH）和白细胞介素（IL）-1β释放增加。进一步的研究表明，TNF-α 显著降低了 let-7 的表达，而 Lin28b 敲低显著增加了 let-7a、let-7d 和 let-7g 的表达。此外，Sirt6 的过表达降低了 Lin28b 的表达。此外，Sirt6 过表达通过减少 TNF-α 诱导的血管内皮细胞中 PI 阳性细胞和 GSDMD 裂解的数量，以及减少 LDH 和 IL-1β 的释放，抑制了细胞焦亡。进一步的机制研究表明，Sirt6 直接与 Lin28b 相互作用并使其去乙酰化。综上所述，这些发现表明 Sirt6 通过负调控 AS 中 Lin28b/let-7 通路抑制血管内皮细胞焦亡。
