TNFAIP2调控巨噬细胞氧化应激促动脉粥样硬化的机制

Coronary syndrome induced by atherosclerosis is now a worldwide disease which is serious threat to human health. Studies show that the vascular regional immune disorder induced by inflammation is very important for atherogenesis. But the mechanism is not clear. TNFAIP2 is a novel gene promoting carcinogenesis. But it’s function in atherogenesis is not clear. Our previous studies showed that TNFAIP2 protein could accelerate atherosclerosis in ApoE-/- mice. To address this issue, in this project macrophages obtained from TNFAIP2-/- and C57 mice treated with or without oxidative stress will be detected the changes of ROS generation, foam cell formation, cell death, inflammatory cytokines secretion, phagocytosis ability, and adhesion functions, to study the mechanism of macrophage functions induced by TNFAIP2. Meanwhile, si-TNFAIP2 lentivirus will be used to determine the effect on atherogenesis induced by blocking TNFAIP2 expression in ApoE-/- mice fead with high-fat-diet. It has great significance for illustrating the mechanism of TNFAIP2 mediated macrophage functions in atherogenesis. It may be helpful for discovering new therapeutic targets for coronary syndrome.

动脉粥样硬化(Atherosclerosis, AS) 所致的冠心病是严重威胁人类健康的世界性疾病，由炎症因素激发血管区域免疫反应是AS形成的重要机制，但确切机制尚不明确。TNFAIP2是具有促肿瘤发生作用的新基因，我们前期以si-TNFAIP2慢病毒转染高脂喂养的ApoE-/-鼠的研究发现，TNFAIP2具有促动脉粥样斑块形成功能。为此，本项目以免疫炎症为切入点，以分离培养的TNFAIP2-/-与WT小鼠腹腔巨噬细胞为靶细胞，研究TNFAIP2基因调控巨噬细胞的炎症因子表达、泡沫化、凋亡、吞噬及清除凋亡碎片、黏附等的效应机制，并探讨干预TNFAIP2表达防治AS的可行性方案，以期发现TNFAIP2在动脉粥样硬化发生中的作用及机制，为揭示冠心病等重大疾病的分子机制、采取有效免疫手段进行防治奠定基础。

动脉粥样硬化(Atherosclerosis, AS) 所致的冠心病是严重威胁人类健康的世界性疾 病，由炎症因素激发血管区域免疫反应是AS形成的重要机制，但确切机制尚不明确。Tnfaip2是具有促肿瘤发生作用的新基因，本课题研究发现Tnfaip2通过调控巨噬细胞功能促进动脉粥样硬化的形成。以分离培养的Tnfaip2-/-与WT小鼠腹腔巨噬细胞或者BMDMs为靶细胞，在H2O2或者CCCP刺激下，发现Tnfaip2的表达上调，且具有时间和剂量依赖性，Tnfaip2过表达能够抵抗氧化应激诱导的细胞凋亡，可能与Tnfaip2具有促进细胞生长进入G2/M细胞周期有关。反之，干扰或缺失Tnfaip2基因表达，细胞生长、克隆形成、细胞迁移均受到抑制，可能与NF-B/MAPK/Akt信号通路的抑制有关。另外，Tnfaip2基因缺失后巨噬细胞的“胞葬作用”明显增强，可能与“eat me”受体如CD36、SR-A、SR-B1上调而”don’t eat me”受体CD47下调有关。在氧化应激环境下，Tnfaip2基因缺失的细胞线粒体功能失稳态，表现为膜电位降低、线粒体ROS生成增加。因此，以si-Tnfaip2慢病毒转染高脂喂养的ApoE-/-鼠的研究发现，干扰Tnfaip2基因表达可以减缓动脉粥样斑块形成，进一步利用骨髓移植实验验证了Tnfaip2的促进AS形成作用。本课题研究结果为探讨动脉粥样硬化的发生机制具有重要意义。