Mu Jianfei, Lin Qinlu, Chen Yajuan, Wang Jianqiang, Yu Xudong, Huang Fang, Liu Xinxin, Fang Yong, Li Yusheng, Zhu Beiwei, Liang Ying
Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China.
College of Food Science and Engineering, Nanjing University of Finance and Economics/Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing, Jiangsu 210023, PR China.
Phytomedicine. 2024 Sep;132:155864. doi: 10.1016/j.phymed.2024.155864. Epub 2024 Jul 14.
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.
The objective of this research is to explore how RBAP impacts cholesterol efflux, which is a considerable element in the advancement of atherosclerosis.
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.
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.
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.
动脉粥样硬化是一种影响动脉壁的慢性炎症性疾病，其特征是脂肪堆积、斑块形成和血管重塑。最近的研究结果凸显了胆固醇清除途径在影响动脉粥样硬化方面的重要性，但胆固醇清除与巨噬细胞炎症调节之间的联系仍知之甚少。RBAP可能作为一种抗炎剂；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充分了解。
本研究的目的是探讨RBAP如何影响胆固醇流出，这是动脉粥样硬化进展中的一个重要因素。
通过使用高脂饮食（HFD）的ApoE基因敲除小鼠建立动脉粥样硬化小鼠模型，以评估口服或注射RBAP的效果。此外，进行了体外实验，诱导THP-1细胞分化为巨噬细胞，并与小鼠RAW264.7细胞一起用氧化型低密度脂蛋白（ox-LDL）进行刺激，以评估RBAP的影响。
在本研究中，发现RBAP可降低动脉粥样硬化模型小鼠以及经ox-LDL刺激的THP-1细胞和小鼠RAW264.7巨噬细胞中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的产生并下调其水平，并抑制Toll样受体4（TLR4）/髓样分化因子88（MyD88）/核因子κB（NF-κB）信号通路的激活。RBAP的有效性还通过增加与胆固醇清除相关的基因过氧化物酶体增殖物激活受体γ（PPARγ）/肝X受体α（LXRα）/ATP结合盒转运体A1（ABCA1）/ATP结合盒转运体G1（ABCG1）的活性，改善了逆向胆固醇转运（RCT）以及胆固醇向高密度脂蛋白（HDL）和载脂蛋白A1（apoA1）的清除，在ApoE小鼠以及THP-1细胞和小鼠RAW264.7巨噬细胞中均如此。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信号抑制剂TAK-242相似。当同时应用RBAP和TAK-242时，与单独使用RBAP或TAK-242治疗相比，改善效果并未增强。
这些发现表明，RBAP作为一种TLR抑制剂，通过改善炎症和促进胆固醇流出具有抗动脉粥样硬化作用，表明其在干预动脉粥样硬化方面的治疗潜力。
