Nrf2调节ABCA1介导的胆固醇逆转运在平滑肌源性泡沫细胞形成中的作用及机制研究

Foam cell formation is the key step of atherosclerosis. Vascular smooth muscle cell（VSMC）is the main source of foam cells in the middle and late stages of atherosclerotic lesions. The mechanism underlying the formation of VSMC foam cell remains to be elucidated. Nuclear factor-erythroid 2- related factor 2（Nrf2）has been demonstrated to inhibit the development of atherosclerosis and associate with the lipid accumulation of macrophage. However, the role of Nrf2 in VSMC-derived foam cell is still unclear. Our previous study found that Nrf2 activation accelerated the cholesterol efflux and inhibited lipid accumulation in VSMC. Herein, we postulate that Nrf2 inbibits the formation of VSMC-derived foam cell, which may be related to increase the ABCA1 expression and promote reverse cholesterol transport（RCT）. In the present study, ApoE-/- mice and VSMC-derived foam cell were used as an atherosclerotic model. The role of Nrf2 in the formation of VSMC foam cell was assessed via manipulating Nrf2 expression using Nrf2-/- mice in vivo and genetic approach in vitro. We also test the hypothesis that Nrf2 up-regulates the ABCA1 expression through increasing PPARγ and subsequently promoting RCT, which ultimately inhibits the VSMC foam cells formation. The present study aims to further investigate the mechanisms of VSMC foam cells formation, and provide new ideas for prevention and treatment of atherosclerosis.

泡沫细胞形成是动脉粥样硬化（AS）发生的关键环节。血管平滑肌细胞（VSMC）源性泡沫细胞作为中晚期AS病变的主要病理细胞，其形成的具体机制远未阐明。现已证实核转录因子Nrf2可抑制AS的发生发展，并与巨噬细胞内脂质聚集有关，但Nrf2是否参与VSMC泡沫样变尚不清楚。前期研究中我们发现活化Nrf2可增加VSMC胆固醇外流，抑制脂质聚集。故我们认为Nrf2可抑制VSMC源性泡沫细胞的形成，其机制可能与上调脂质转运体ABCA1表达，促进胆固醇逆转运（RCT）有关。据此，本项目拟建立VSMC源性泡沫细胞模型和ApoE-/-小鼠模型，采用Nrf2-/-小鼠和基因工程技术控制Nrf2表达，明确Nrf2在VSMC源性泡沫细胞形成中的作用，并探讨Nrf2是否通过PPARγ上调ABCA1表达，促进RCT过程，进而抑制泡沫细胞形成。旨在深入研究VSMC源性泡沫细胞形成的分子机制，以期为AS的防治提供新思路。

本研究从胆固醇逆转运（Reverse cholesterol transport，RCT）这一调控胞内胆固醇转运的关键环节入手，明确了过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor γ，PPARγ）上调脂质转运体ABCG1表达，促进RCT过程，进而抑制血管平滑肌细胞（VSMCs）源性泡沫细胞形成的作用机制。与此同时，阐明了PPARδ通过下调胆固醇酰基转移酶1（ACAT1）抑制VSMCs源性泡沫细胞形成的分子机制。进一步，分析了Nrf2在调节VSMCs源性泡沫细胞形成中的作用，并通过应用TLR4基因敲除小鼠和基因工程技术控制TLR4表达，明确了TLR4在VSMCs源性泡沫细胞形成中的作用，证实了TLR4通过PPARγ下调ABCG1表达，进而促进VSMCs源性泡沫细胞形成的作用机制。研究后期，从VSMCs源性泡沫细胞迁移这一全新的角度，分析了VSMCs源性泡沫细胞迁移在动脉粥样硬化形成中的作用，并阐明了瞬时受体电位香草醛亚家族1（TRPV1）通过上调去乙酰化酶1（SIRT1）表达和下调NF-κB信号抑制VSMCs源性泡沫细胞迁移的作用机制。本课题深入研究了VSMCs源性泡沫细胞在动脉粥样硬化形成中的具体作用和分子机制，为寻找新的动脉粥样硬化防治干预靶点提供了重要的理论依据。研究结果在国外SCI期刊发表论文3篇（总影响因子：11.305），国内CSCD期刊发表论文3篇。