血管外膜脂肪组织Omentin-1对巨噬细胞自噬和动脉粥样硬化斑块稳定性的影响及机制

Macrophage autophagy plays a major protective role in modulating atherosclerotic plaque stability, which is the leading cause of atherosclerosis-related death. Perivascular adipose tissue (PVAT) is the fat tissue surrounding vasculature and it has been proved that PAVT can affect the development of atherosclerosis and plaque stability. Similar to other fat depots, PAVT secrets numerous pro- or anti-inflammatory adipokines that can act in both endocrine and paracrine fashion. Whether macrophage authophagy can be regulated by adipokines and mediates their effect on atherosclerosis is not clear. Omentin-1, an anti-inflammatory adipokine abundantly expressed in PAVT, is found in our previous investigations significantly downregulated in the adipose tissue surrounding atherosclerotic plaques, indicating its close relationship with atherosclerosis. Current evidence shows that ometin-1 suppresses oxidized low-density lipoprotein-induced foam cell formation and macrophage apoptosis. However, there have been no previous reports regarding the effects of omentin-1 on plaque stability as well as its mechanism. Additionally, the regulation of omentin-1 expression in PAVT by atherosclerosis is not known. In this project, we seek to evaluate the effect of omentin-1 on mice macrophage autophagy and its signaling pathway. Furthermore, the effect of omentin-1 on macrophage autophagy and plaque stability, as well as the regulation of omentin-1 expression in PAVT by atherosclerosis, will be investigated in apolipoprotein E-deficient mice vulnerable plaque model. This project will provide further evidence for the crosstalk between PAVT and atherosclerosis, and help us find a novel target for prevention or treatment of atherosclerosis.

动脉粥样硬化（AS）的进程与斑块稳定性紧密相关，巨噬细胞（MP）自噬对于维持斑块稳定性至关重要。脂肪组织分泌的脂肪因子与AS进展关系密切，阐述相关脂肪因子是否通过MP自噬调控斑块稳定性对AS治疗具重要意义。Omentin-1是一种保护性脂肪因子，我们前期研究显示其主要在血管外膜脂肪组织（PAVT）表达，且表达水平受AS负调控，推测其可能在AS中扮演重要角色。目前发现Omentin-1对泡沫细胞形成、MP凋亡有抑制作用，但其在体内对斑块稳定性的影响及作用机制尚不清晰，AS病程中PAVT表达Omentin-1的调控方式并不明确。本项目拟研究Omentin-1对小鼠MP自噬的影响及其信号途径，并应用apoE-/-小鼠不稳定斑块模型，研究Omentin-1是否通过调控MP自噬改善斑块稳定性，同时观察并进一步阐明Omentin-1在AS发生发展过程中的调控机理，为AS临床治疗方法的更新提出新的思路。

Omentin-1是一种主要由内脏脂肪组织释放的新型细胞因子。已有研究表明，Omentin-1的表达与心血管疾病的发生发展密切相关，本课题旨在探讨Omentin-1对ApoE-/-小鼠动脉粥样硬化斑块稳定性的影响及其机制。通过将微量渗透泵植入ApoE-/-小鼠体内，并模拟生理状态下Omentin-1的持续性分泌，我们得以观察Omentin-1对已形成的AS斑块表型的影响。动物实验表明，注射Omentin-1可增加ApoE-/-小鼠AS斑块的胶原含量、平均纤维帽厚度并减轻坏死核心的形成。免疫组化分析显示，静脉输注Omentin-1可抑制斑块内炎性细胞因子的表达。免疫共沉淀实验和共聚焦显微镜分析证实了Omentin-1与整合素受体αvβ3和αvβ5的结合。细胞研究表明，Omentin-1能抑制氧化型低密度脂蛋白诱导的巨噬细胞凋亡和炎性细胞因子的分泌。此外，Ometin-1能促进巨噬细胞整合素相关信号通路的磷酸化。在整合素受体中加入抑制剂或干扰整合素亚单位αv的表达均显著抑制了Omentin-1诱导的生物效应。此外，流式细胞仪分析表明，Omentin-1可抑制巨噬细胞胞葬功能的活性。结论：脂肪因子Omentin-1可抑制AS病变内坏死核的形成和促炎细胞因子的表达，并增加坏死核心的纤维帽厚度和斑块内胶原纤维的含量。可能的机制为通过与整合素受体αvβ3和αvβ5直接结合抑制巨噬细胞凋亡、泡沫化水平和促炎性细胞因子的分泌。脂肪因子Omentin-1不是胞葬过程中的桥接分子，Omentin-1的加入减弱了巨噬细胞的胞葬活性。