Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy.
Department of Molecular Medicine, University of Pavia, Via C. Forlanini 6, 27100 Pavia, Italy.
Int J Mol Sci. 2023 Apr 4;24(7):6759. doi: 10.3390/ijms24076759.
Sirtuin 6 (SIRT6) is a member of the mammalian NAD-dependent deac(et)ylase sirtuin family. SIRT6's anti-inflammatory roles are emerging increasingly often in different diseases and cell types, including endothelial cells. In this study, the role of SIRT6 in pro-inflammatory conditions was investigated by engineering human umbilical vein endothelial cells to overexpress SIRT6 (SIRT6+ HUVECs). Our results showed that SIRT6 overexpression affected the levels of adhesion molecules and sustained megakaryocyte proliferation and proplatelet formation. Interestingly, the pro-inflammatory activation of the ATP/purinergic axis was reduced in SIRT6+ HUVECs. Specifically, the TNFα-induced release of ATP in the extracellular space and the increase in pannexin-1 hemichannel expression, which mediates ATP efflux, were hampered in SIRT6+ cells. Instead, NAD release and Connexin43 expression were not modified by SIRT6 levels. Moreover, the Ca influx in response to ATP and the expression of the purinergic receptor P2X7 were decreased in SIRT6+ HUVECs. Contrary to extracellular ATP, extracellular NAD did not evoke pro-inflammatory responses in HUVECs. Instead, NAD administration reduced endothelial cell proliferation and motility and counteracted the TNFα-induced angiogenesis. Altogether, our data reinforce the view of SIRT6 activation as an anti-inflammatory approach in vascular endothelium.
Sirtuin 6 (SIRT6) 是哺乳动物 NAD 依赖性去乙酰化酶 sirtuin 家族的成员。SIRT6 在不同疾病和细胞类型中的抗炎作用越来越受到关注，包括内皮细胞。在这项研究中，通过工程化人脐静脉内皮细胞过表达 SIRT6（SIRT6+ HUVECs）来研究 SIRT6 在促炎条件下的作用。我们的结果表明，SIRT6 的过表达影响了粘附分子的水平，并维持巨核细胞的增殖和前血小板的形成。有趣的是，SIRT6+ HUVECs 中 ATP/嘌呤能轴的促炎激活被减弱。具体而言，SIRT6 细胞中 TNFα 诱导的细胞外空间中 ATP 的释放以及介导 ATP 外排的连接蛋白 1 半通道表达的增加受到阻碍。相反，SIRT6 水平不改变 NAD 释放和连接蛋白 43 的表达。此外，SIRT6+ HUVECs 中对 ATP 的 Ca2+ 内流和嘌呤能受体 P2X7 的表达减少。与细胞外 ATP 相反，细胞外 NAD 不会在 HUVECs 中引发促炎反应。相反，NAD 的给药减少了内皮细胞的增殖和迁移，并拮抗了 TNFα 诱导的血管生成。总的来说，我们的数据强化了 SIRT6 激活作为血管内皮抗炎方法的观点。
