背景:动脉粥样硬化是一种影响动脉壁的长期炎症性疾病,以脂肪的积累为标志,斑块形成,和血管重塑。最近的发现强调了胆固醇去除途径在影响动脉粥样硬化中的意义。然而,胆固醇去除和调节巨噬细胞炎症之间的联系仍然知之甚少。RBAP可以作为抗炎剂;然而,其在动脉粥样硬化中的作用及其背后的机制仍未得到很好的理解。
目的:本研究的目的是探索RBAP如何影响胆固醇流出,这是动脉粥样硬化发展的重要因素。
方法:使用高脂饮食(HFD)的ApoEKO品系小鼠建立动脉粥样硬化小鼠模型,以评估RBAP的作用,通过口服或注射进行。此外,进行了体外实验,其中诱导THP-1细胞向巨噬细胞分化,以及小鼠RAW264.7细胞,用ox-LDL来评估RBAP的影响。
结果:在这项研究中,发现RBAP可减少TNF-α的产生并下调,IL-1β,并抑制动脉粥样硬化模型小鼠TLR4/MyD88/NF-κB信号的激活,以及在ox-LDL攻击的THP-1细胞和小鼠RAW264.7巨噬细胞中。RBAP的有效性还通过增加ApoE-/-小鼠和THP-1细胞和小鼠RAW264.7巨噬细胞中与胆固醇去除相关的基因PPARγ/LXRα/ABCA1/ABCG1的活性,改善了胆固醇反向转运(RCT)和胆固醇向HDL和apoA1的去除的增强。值得注意的是,RBAP对动脉粥样硬化模型小鼠和巨噬细胞的作用与TLR4信号传导抑制剂TAK-242相似。当RBAP和TAK-242同时应用时,与RBAP或TAK-242单独治疗相比,改善没有增强.
结论:这些发现表明RBAP,作为TLR4抑制剂,通过改善炎症和促进胆固醇作用,具有抗动脉粥样硬化作用,表明其在干预动脉粥样硬化中的治疗潜力。
BACKGROUND: Atherosclerosis is a long-lasting inflammatory condition affecting the walls of arteries, marked by the buildup of fats, plaque formation, and vascular remodeling. Recent findings highlight the significance of cholesterol removal pathways in influencing atherosclerosis, yet the connection between cholesterol removal and regulation of macrophage inflammation remains poorly understood. RBAP could serve as an anti-inflammatory agent; however, its role in atherosclerosis and the mechanism behind it are still not well understood.
OBJECTIVE: The objective of this research is to explore how RBAP impacts cholesterol efflux, which is a considerable element in the advancement of atherosclerosis.
METHODS: An atherosclerosis mouse model was established by using an ApoE KO strain mouse on a high-fat diet (HFD) to assess the effects of RBAP, conducted either orally or through injection. Additionally, in vitro experiments were conducted where the induction of THP-1 cells was conducted for the differentiation towards macrophages, and along with mouse RAW264.7 cells, were challenged with ox-LDL to evaluate the impact of RBAP.
RESULTS: In this study, RBAP was found to reduce the production and downregulate TNF-α, IL-1β, and IL-6 levels and inhibited the activation of the TLR4/MyD88/NF-κB signaling in atherosclerosis model mice, as well as in ox-LDL-challenged THP-1 cells and mouse RAW264.7 macrophages. RBAP\'s effectiveness also improved the enhancement of reverse cholesterol transport (RCT) and cholesterol removal to HDL and apoA1 by increasing the activity of genes related to cholesterol removal PPARγ/LXRα/ABCA1/ABCG1, both in ApoE-/- mice and in THP-1 cells and mouse RAW264.7 macrophages. Notably, RBAP exerted similar effects on atherosclerosis model mice and macrophages to those of TAK-242, an inhibitor of the TLR4 signaling. When RBAP and TAK-242 were applied simultaneously, the improvement was not enhanced compared with either RBAP or TAK-242 treatment alone.
CONCLUSIONS: These findings suggest that RBAP, as a TLR4 inhibitor, has anti-atherosclerotic effects by improving inflammation and promoting cholesterol effection, indicating its therapeutic potential in intervening atherosclerosis.