SIRT6 inhibits cholesterol crystal-induced vascular endothelial dysfunction via Nrf2 activation
SIRT6 inhibits cholesterol crystal-induced vascular endothelial dysfunction via Nrf2 activation
复制标题
SIRT6 通过 Nrf2 激活抑制胆固醇晶体诱导的血管内皮功能障碍
DOI：
10.1016/j.yexcr.2019.111744
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发表时间：
2020-02-01
影响因子：
3.7
通讯作者：
Lin, Rong
中科院分区：
文献类型：
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作者：
Jin, Zhen;Xiao, Yunfang;Lin, Rong
Sirtuin 6（SIRT6）是一种烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶，参与多种与年龄相关的疾病，如血脂异常和心血管疾病。最近的研究表明，微小的胆固醇晶体（CC），这是多余的游离胆固醇积累后产生的，不仅在成熟的动脉粥样硬化斑块中形成，而且在动脉粥样硬化的极早期。由于内皮功能障碍是动脉粥样硬化形成的早期特征，本研究旨在研究SIRT6在CC诱导的内皮功能障碍中的作用及其相关机制。我们发现，微小的CC可以被内皮细胞（ECs）内吞，然后降低一氧化氮（NO）水平和内皮型一氧化氮合酶（eNOS）的活性和表达，上调粘附分子的表达，增强单核细胞粘附到ECs。此外，微小CC显著抑制EC中SIRT6的表达。此外，SIRT6的过表达可以减轻CC诱导的内皮功能障碍。此外，核因子红细胞2相关因子2（Nrf2）的表达被抑制后，分钟CC治疗，而SIRT6过表达逆转这种减少Nrf2的表达。更重要的是，Nrf2激活也显着衰减分钟CC诱导的内皮功能障碍。体内实验进一步表明，内皮特异性SIRT6耗竭损害血管内皮功能并抑制高血压小鼠中的Nrf2表达。总之，这些结果表明SIRT6部分地通过Nrf2激活来挽救微小的CC诱导的内皮功能障碍。
Sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide-dependent deacetylase, participates in various age-related disorders, such as dyslipidemia and cardiovascular diseases. Recent studies have revealed that minute cholesterol crystals (CCs), which are generated after excess free cholesterol accumulation, form not only in mature atherosclerotic plaques but also extremely early in atherosclerosis. Since endothelial dysfunction is an early feature of atherogenesis, this study was designed to investigate the role of SIRT6 in minute CC-induced endothelial dysfunction and the related mechanism. We found that minute CCs could be endocytosed by endothelial cells (ECs), which then decreased nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activity and expression, upregulated the expression of adhesion molecules and enhanced monocyte adhesion to ECs. In addition, minute CCs significantly suppressed SIRT6 expression in ECs. Moreover, the overexpression of SIRT6 could mitigate minute CC-induced endothelial dysfunction. In addition, the expression of Nuclear factor erythroid2-related factor2 (Nrf2) was suppressed after minute CC treatment, whereas SIRT6 overexpression reversed this decrease in Nrf2 expression. More importantly, Nrf2 activation also notably attenuated minute CC-induced endothelial dysfunction. In vivo experiments further indicated that endothelium-specific SIRT6 depletion impaired vascular endothelial function and suppressed Nrf2 expression in hyperlipidemic mice. Taken together, these results indicate that SIRT6 rescues minute CC-induced endothelial dysfunction partly via Nrf2 activation.