Nrf2依赖性调控巨噬细胞胆固醇代谢及解毒表型极化在莱菔硫烷抑制动脉粥样硬化性心血管疾病中的作用

Macrophages are essential players in progression of atherosclerotic cardiovascular disease (ASCVD). Exploring bioactive food components that can induce an AS protective phenotype transformation of macrophage, will provide scientific evidence for effective prevention and treatment of ASCVD. In the previous study, we confirmed that sulforaphane (SFN) is an inducer of Nrf2 and upregulates several antioxidant enzymes expression such as HO-1 via Nrf2 activation. Besides, it was suggested that the key genes involved in macrophage cholesterol metabolism, including CD36, PPARγ and ABCA1/G1, are potential targets of Nrf2. We have also demonstrated that cholesterol efflux from macrophage mediated by ABCA1/G1 can inhibit AS progression. However, it remains unknown whether SFN can in a Nrf2 dependent manner induce a macrophage phenotype polarized to cholesterol metabolism and detoxication, thus inhibiting AS progression. Therefore, in the current project, THP-1 derived macrophage overloaded by oxLDL and ApoE-/- mice will be used as models to verify whether SFN can Nrf2 dependently induce a macrophage phenotype, characterized by high level expressions of CD36, PPARγ, ABCA1/G1, HO-1 and low level expressions of IL-6, TNF-α and so on, so that increase phagocytosis and clearance of oxLDL, meanwhile alleviate intracellular lipid load and stress reaction, thus inhibiting AS plaque formation and enhancing its stability.

巨噬细胞在动脉粥样硬化(AS)性心血管疾病(ASCVD)发展中起核心作用，探寻可诱导其向AS保护性表型极化的食物活性成分，将为ASCVD防治提供科学依据。我们前期证实莱菔硫烷（SFN）为Nrf2诱导剂，可Nrf2依赖性上调HO-1等多种抗氧化物酶表达。而研究提示巨噬细胞胆固醇代谢关键基因CD36、PPARγ、ABCA1/G1等均为Nrf2潜在靶点。我们亦证实ABCA1/G1介导巨噬细胞胆固醇外流可抑制AS进展。而SFN能否通过Nrf2调控巨噬细胞胆固醇代谢及解毒表型极化，抑制AS进展？迄今未见报道。本研究拟以THP-1细胞、ApoE-/-小鼠为模型，观察SFN能否通过Nrf2依赖性诱导巨噬细胞向以CD36、PPARγ、ABCA1/G1、HO-1等高表达，IL-6、TNF-α等低表达为特点的表型极化，从而增加oxLDL吞噬清除同时，缓解胞内脂质负荷及应激反应，抑制AS斑块形成并增加其稳定性。

动脉粥样硬化（AS）构成心血管疾病(CVD)最主要病理学基础，是全球范围内首要死因构成，而巨噬泡沫细胞形成、巨噬细胞表型和功能改变在此过程中发挥核心作用。十字花科蔬菜主要活性成分莱菔硫烷（SFN）被证实具有CVD保护效应，但目前未见其对巨噬泡沫细胞形成及AS斑块形成影响及机制的研究报道。本项目采用体外ox-LDL负荷THP-1、J774A.1巨噬细胞及高脂饲喂ApoE-/-小鼠模型，证实SFN干预可显著抑制巨噬泡沫细胞形成及相应脂毒性、抑制AS斑块的形成及不稳定性表型；而主要的分子机制涉及SFN诱导HO-1、ABCA1/G1高表达、CD36低表达巨噬细胞表型，进而促进ApoA-1和HDL介导的巨噬细胞胆固醇外流、抑制其胆固醇摄入，以及增强其应激防御能力，而这主要依赖于SFN对转录因子Nrf2和PPARγ的综合性调控。我们的研究发现拓展了人们对SFN防治心血管代谢性疾病效应和机制的认识，并为鼓励充足的十字花科蔬菜摄入促进健康提供了重要的理论依据。