Brd2调控巨噬细胞新的死亡方式—pyroptosis在动脉粥样硬化中的作用和机制

Cell death and inflammation are important in development of atherosclerosis. Pyroptosis is a novel form of cell death which is uniquely companied by inflammation. We have previously confirmed that oxidized low density lipoprotein could induced macrophage pyroptosis, which play an important role in atherosclerotic lesion instability. Brd2, the main member of BET family, has been recently found to be closely related with macrophages death and inflammation. Our previous studies found that oxidized low density lipoprotein induced the abundant expression of Brd2, IL-1β and IL-18 in human macrophages; blocking Brd2 reversed the elevated release of IL-1β and IL-18 in macrophages. Results collectively suggest a potential role of Brd2 in macrophage pyroptosis and atherosclerotic inflammation; however, the underlying mechanism remains largely unkonwn. The aim of these study is to investigate: 1) the expression of Brd2 and its relationship with macrophage pyroptosis and inflammation in atherosclerosis;2) the role and mechanism of Brd2 in oxidized low density lipoprotein induced macrophage pyroptosis and the signal pathway. The results will clarify the regulatory mechanism of macrophage pyroptosis in atherosclerosis and may lead to new therapeutic approaches in prevention and treatment of atherosclerosis.

细胞死亡及炎症反应与动脉粥样硬化（AS）密切相关。Pyroptosis是新近发现的一种伴随炎症反应的细胞死亡方式。我们前期研究证实ox-LDL可诱导巨噬细胞发生pyroptosis, 可能在AS斑块不稳定中发挥重要作用。近年来研究表明,溴结构域蛋白家族成员Brd2与巨噬细胞炎症反应及死亡密切相关。我们的预实验发现，ox-LDL诱导巨噬细胞Brd2、IL-1β和IL-18表达增加；阻断Brd2，IL-1β和IL-18表达下降。上述研究强烈提示Brd2参与AS巨噬细胞pyroptosis及炎症反应的发生。本研究将通过在体和细胞实验观察：1) AS中Brd2表达规律，其与巨噬细胞pyroptosis和炎症反应的关系；2) Brd2在ox-LDL诱导的巨噬细胞pyroptosis中的作用和信号通道，来阐明AS时巨噬细胞pyroptosis的调控机制，为以Brd2为靶点防治AS提供理论依据。

动脉粥样硬化是一种慢性炎症性疾病。细胞死亡与动脉粥样硬化发生发展密切相关。研究已证实细胞焦亡是一种与炎症反应密切相关的细胞死亡方式，是动脉粥样硬化斑块不稳定的重要机制。BET 是一类能够识别乙酰化修饰的蛋白家族，广泛参与细胞周期、细胞分化、炎症反应、肿瘤发生等过程。.在为期三年的研究中，我们首次发现抑制BET能够延缓高脂饲养ApoE-/-小鼠动脉粥样硬化发生发展。进一步研究发现抑制BET减轻ApoE-/-小鼠动脉粥样硬化斑块中细胞死亡及炎症反应，对ApoE-/-动脉粥样硬化小鼠T细胞反应类型无明显影响。体外研究证实抑制BET可减轻氧化型低密度脂蛋白诱导的巨噬细胞焦亡死亡方式。以上研究表明BET蛋白家族可成为调控动脉粥样硬化新靶点之一。