Atherosclerosis caused major morbidity and mortality worldwide. Molecules possessing lipid-lowering and/or anti-inflammatory properties are potential druggable targets against atherosclerosis. We examined the anti-atherosclerotic effects of fluorescent gold nanoclusters (FANC), which were dihydrolipoic acid (DHLA)-capped 2-nm gold nanoparticles. We evaluated the 8-week effects of FANC in Western-type diet-fed ApoE-deficient mice by either continuous intraperitoneal delivery (20 μM, 50 μl weekly) or via drinking water (300 nM). FANC reduced aortic atheroma burden, serum total cholesterol, and oxidative stress markers malondialdehyde and 4-hydroxynonenal levels. FANC attenuated hepatic lipid deposit, with changed expression of lipid homeostasis-related genes HMGCR, SREBP, PCSK9, and LDLR in a pattern similar to mice treated with ezetimibe. FANC also inhibited intestinal cholesterol absorption, resembling the action of ezetimibe. The lipid-lowering and anti-atherosclerotic effects of FANC reappeared in Western-type diet-fed LDLr-deficient mice. FANC bound insulin receptor β (IRβ) via DHLA, leading to AKT activation. However, unlike insulin, which also bound IRβ to activate AKT to induce HO-1, activation of AKT by FANC was independent of HO-1 expression in human aortic endothelial cells (HAECs). Alternatively, FANC up-regulated NRF2, interfered the binding of KEAP1 to NRF2, and promoted KEAP1 degradation to free NRF2 for nuclear entry to induce HO-1 that suppressed the expression of ICAM-1 and VCAM-1. Consistently, FANC suppressed ox-LDL-induced enhanced attachment of THP-derived macrophages onto HAECs. In macrophages, FANC up-regulated ABCA1, and reversed ox-LDL-induced suppression of cholesterol efflux. FANC effected in vitro at nano moles. In conclusion, our findings showed novel actions and multiple mechanisms of FANC worked coherently against atherosclerosis.

中文翻译：

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荧光金纳米团簇具有对抗动脉粥样硬化的多种作用


动脉粥样硬化在世界范围内造成了严重的发病率和死亡率。具有降脂和/或抗炎特性的分子是对抗动脉粥样硬化的潜在成药靶点。我们检查了荧光金纳米簇 （FANC） 的抗动脉粥样硬化作用，FANC 是二氢硫辛酸 （DHLA） 封端的 2 nm 金纳米颗粒。我们通过连续腹膜内输送 （20 μM，每周 50 μl） 或通过饮用水 （300 nM） 评估了 FANC 对西式饮食喂养的 ApoE 缺陷小鼠的 8 周影响。FANC 降低了主动脉粥样硬化负荷、血清总胆固醇和氧化应激标志物丙二醛和 4-羟基壬烯醛水平。FANC 减弱肝脏脂质沉积，脂质稳态相关基因 HMGCR 、 SREBP 、 PCSK9 和 LDLR 的表达发生变化，其模式类似于用依折麦布处理的小鼠。FANC 还抑制肠道胆固醇吸收，类似于依折麦布的作用。FANC 的降脂和抗动脉粥样硬化作用在西式饮食喂养的 LDLr 缺陷小鼠中再次出现。FANC 通过 DHLA 结合胰岛素受体 β （IRβ），导致 AKT 激活。然而，与胰岛素不同，胰岛素也结合 IRβ 激活 AKT 以诱导 HO-1，FANC 激活 AKT 与人主动脉内皮细胞 （HAEC） 中 HO-1 的表达无关。或者，FANC 上调 NRF2，干扰 KEAP1 与 NRF2 的结合，并促进 KEAP1 降解为游离 NRF2 以进入核，以诱导抑制 ICAM-1 和 VCAM-1 表达的 HO-1。始终如一，FANC 抑制了 ox-LDL 诱导的 THP 衍生巨噬细胞对 HAEC 的附着增强。在巨噬细胞中，FANC 上调 ABCA1，并逆转 ox-LDL 诱导的胆固醇外流抑制。FANC 在体外对纳米摩尔产生影响。 总之，我们的研究结果表明 FANC 的新作用和多种机制对动脉粥样硬化起作用。