Sirt6 inhibits vascular endothelial cell pyroptosis by regulation of the Lin28b/let-7 pathway in atherosclerosis.

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.