Sirt6 has been reported to play a protective role in macrophage foam cell formation, but whether Sirt6 controls atherosclerosis plaque stability and whether it can reduce the interaction between endothelial cells and macrophages remains unclear. The aim of this study was to investigate the effect of Sirt6 on atherosclerosis plaque stability and the underlying mechanisms. We used Tie2-Cre transgenic mice as a Cre-lox tool to delete Sirt6 floxed sequences in endothelial cells during adulthood to establish Sirt6-/- mice. ApoE-/-:Sirt6-/- and ApoE-/-:Sirt6Tg mice were used in our investigation. After a 16 week high-fat diet, the mice developed markedly atherosclerotic plaques. Sirt6 knockout exacerbated atherosclerotic plaque progression in both size and stability. In vitro, murine macrophage RAW264.7 cells were treated with ox-low density lipoproteins for 24 h to simulate atherosclerosis. Furthermore, Sirt6 overexpression remarkably increased autophagic flux in macrophages and inhibited macrophage apoptosis. Moreover, Sirt6 overexpression inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet selectin (P-selectin), leading to reduced infiltration of macrophages and foam cells. In conclusion, our study indicates a new mechanism-based strategy to therapeutically stimulate atherosclerosis plaque stability.

中文翻译：

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Sirt6通过促进巨噬细胞自噬并减少与内皮细胞的接触来稳定动脉粥样硬化斑块。

据报道，Sirt6在巨噬细胞泡沫细胞形成中起保护作用，但是尚不清楚Sirt6是否控制动脉粥样硬化斑块的稳定性以及它是否可以减少内皮细胞与巨噬细胞之间的相互作用。这项研究的目的是调查Sirt6对动脉粥样硬化斑块稳定性及其潜在机制的影响。我们使用Tie2-Cre转基因小鼠作为Cre-lox工具，以在成年期间删除内皮细胞中的Sirt6固定序列，以建立Sirt6-/-小鼠。ApoE-/-：Sirt6-/-和ApoE-/-：Sirt6Tg小鼠用于我们的研究。经过16周的高脂饮食，小鼠出现明显的动脉粥样硬化斑块。Sirt6基因敲除加剧了动脉粥样硬化斑块的大小和稳定性。在体外，鼠巨噬细胞RAW264。用低密度低密度脂蛋白处理7个细胞24小时，以模拟动脉粥样硬化。此外，Sirt6的过表达显着增加巨噬细胞中的自噬通量，并抑制巨噬细胞凋亡。此外，Sirt6的过表达抑制了血管细胞粘附分子1（VCAM-1），细胞间粘附分子1（ICAM-1）和血小板选择素（P-selectin）的表达，从而导致巨噬细胞和泡沫细胞的浸润减少。总之，我们的研究表明了一种新的基于机制的策略来治疗性地刺激动脉粥样硬化斑块的稳定性。细胞间黏附分子-1（ICAM-1）和血小板选择素（P-selectin），导致巨噬细胞和泡沫细胞的浸润减少。总之，我们的研究表明了一种新的基于机制的策略来治疗性地刺激动脉粥样硬化斑块的稳定性。细胞间黏附分子-1（ICAM-1）和血小板选择素（P-selectin），导致巨噬细胞和泡沫细胞的浸润减少。总之，我们的研究表明了一种新的基于机制的策略来治疗性地刺激动脉粥样硬化斑块的稳定性。