虾青素经胆固醇逆向转运对动脉粥样硬化的影响及其机制研究

Atherosclerosis (AS) is closely linked to the dietary nutrition. Bioactive components have important prevention of AS in dietary. Recent studies have shown that elevating plasma high-density lipoprotein cholesterol (HDL-C) level was helpful for the prevention and treatment of AS, while the promotion of reverse cholesterol transport (RCT) was proved to be one of the most important mechanisms that antiatherosclerosis of HDL-C. Astaxanthin is a non-provitamin A carotenoids, which can decrease the plaque area of the aortic sinus in ApoE-/- mice in our previous study, but the mechanism of action still unknown. Base on above, the followings will be investigated. First, the relationship between astaxanthin antiatherosclerosis and regulating macrophage RCT in ApoE-/- mice. Second, the effects of astaxanthin on cholesterol efflux and expression of ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1) and scavenger receptor class B type I; as well as the influence of astaxanthin on a signaling pathway called LXRα-ABCA1/ABCG1 and related microRNA in different macrophage model. At last, the relationship among astaxanthin antiatherosclerosis, regulating macrophage RCT and related microRNA in hypercholesterolemia patients. These results will provide scientific evidence for applying astaxanthin to prevent the generation and development of AS.

动脉粥样硬化（AS）与营养膳食密切相关，膳食中生物活性成分对AS具有重要预防作用。近期研究表明，提高血浆高密度脂蛋白胆固醇（HDL-C）水平有利于防治AS，而促进巨噬细胞胆固醇逆向转运（RCT）被证实是HDL-C抗AS重要机制之一。虾青素是一种非维生素A原类胡萝卜素，我们前期研究发现其可减少ApoE-/-小鼠主动脉AS斑块面积，但作用机制尚不清楚。基于此，本课题拟在1）ApoE-/-小鼠，研究虾青素抗AS与调节巨噬细胞RCT的关系。2）不同巨噬细胞模型，探讨虾青素对胆固醇外流中ATP结合盒转运体A1、G1（ABCA1、ABCG1）和B族I型清道夫受体等表达，以及肝X受体α-ABCA1/ABCG1信号通路和相关microRNA的影响。3）高胆固醇血症患者，验证虾青素抗AS与调节巨噬细胞RCT及其与相关microRNA的关系。研究结果将为应用虾青素预防AS的发生和发展提供科学依据。

动脉粥样硬化（AS）所致心血管疾病严重威胁人类健康。血浆高密度脂蛋白胆固醇（HDL-C）水平与AS的风险降低有关，HDL-C被认为是抗AS的脂蛋白。提高HDL水平可进一步降低AS风险，胆固醇逆向转运（RCT）被认为是HDL抗AS的重要机制。RCT主要通过ATP结合盒转运蛋白A1（ABCA1），ATP结合盒转运蛋白G1（ABCG1）和B族I型清道夫受体（SR-BI）促进巨噬泡沫细胞胆固醇外流，然后经肝脏排泄至胆汁并最终进入粪便。AS与营养膳食密切相关，膳食生物活性成分对AS有重要预防作用。虾青素是一种非维生素A原的类胡萝卜素，我们已证实它能提高小鼠血浆HDL-C水平。本研究首先通过C57BL/6J和ApoE-/-小鼠，研究虾青素抗AS与调节巨噬细胞RCT的关系。结果发现，短期和长期的虾青素补充分别促进C57BL/6J和ApoE-/-小鼠的RCT。而且，虾青素可以减轻ApoE-/-小鼠主动脉AS斑块面积和胆固醇含量。然后通过THP-1和RAW264.7细胞模型，探讨虾青素对胆固醇外流ABCA1、ABCG1和SR-BI等表达，以及相关miRNA、circRNA表达的影响。结果发现，虾青素促进THP-1细胞胆固醇外流时circPCMTD1通过靶向miR-5581-3p调控ABCA1基因发挥作用，虾青素促进RAW264.7细胞胆固醇外流时circTPP2通过靶向miR-3073b-5p调控ABCA1基因发挥作用。因此，虾青素可以改善ApoE-/-小鼠巨噬细胞RCT效率和抑制AS斑块形成，其机制可能与调控circPCMTD1/miR-5581-3p/ABCA1或者circTPP2/miR-3073b-5p/ABCA1信号通路有关。另外，20 mg/d虾青素干预12周对血脂紊乱人群的血脂水平有一定改善作用。研究结果将为应用虾青素预防AS的发生发展提供科学依据。