S100A12及其受体RAGE在动脉粥样硬化发生中的作用及机制研究

Coronary atherosclerotic heart disease is the most common diseases in the cardiovascular system.Macrophages apoptosis in atherosclerotic plaques continuing to accumulate and motivating necrosis leads to the unstable plaque, but its mechanism has not been elucidated.Our preliminary experimental results show that S100A12 and its receptor RAGE highly express in human coronary atherosclerotic plaque,especially in the apoptosis of macrophages, which suggests S100A12 and its receptor RAGE may be involved in the process of atherosclerosis by affecting the macrophage apoptosis.Our study try to establish the transgenic mouse model which has the S100A12 specifically expressing in macrophages to validate that S100A12 influencing the formation of atherosclerotic unstable plaque by activating the macrophage apoptosis.And in vivo and in vitro level we validate the S100A12 combination with its receptor RAGE by activating P53 apoptosis signal transduction pathways induce and promot the macrophage apoptosis, leading to the formation of unstable atherosclerotic plaque. Through our study, it can be further clarified that S100A12 and its receptor RAGE can activate the P53 pathway to regulate the macrophage apoptosis and influence the forming process of atherosclerotic plaque.So targeting macrophage apoptosis may be useful in the treatment of atherosclerosis.

冠状动脉粥样硬化是心血管系统疾病中最常见的疾病，粥样硬化斑块中巨噬细胞凋亡的持续积累及其激发性坏死是导致动脉粥样硬化不稳定斑块形成的重要原因，但其发生机制尚未阐明。我们预实验的结果显示S100A12及其受体RAGE在人冠状动脉粥样硬化斑块凋亡的巨噬细胞中大量表达，提示S100A12及其受体RAGE可能通过影响巨噬细胞的凋亡参与动脉粥样硬化的进程。本研究尝试在巨噬细胞特异性表达的S100A12转基因小鼠模型中验证S100A12通过RAGE受体促进巨噬细胞的凋亡诱导动脉粥样硬化不稳定斑块的形成；并通过在体和离体水平验证S100A12与其受体RAGE结合后通过激活P53凋亡信号转导途径诱导和促进巨噬细胞的调亡，进而导致动脉粥样硬化不稳定斑块的形成。本研究的顺利完成，能深入揭示S100A12与其受体RAGE在动脉粥样硬化中调控巨噬细胞凋亡的作用及其机制，为动脉粥样硬化性疾病的防治提供新的思路。

冠状动脉粥样硬化病变部位的斑块持续增大，粥样硬化的不稳定斑块破裂、出血导致管腔内血栓形成，阻塞冠状动脉血管导致心肌细胞的缺血缺氧，因而引起急性心肌梗死（AMI）的发生。S100A12在ST段抬高型急性心肌梗死（STEMI）发病30min即出现升高，STEMI发病2h内诊断STEMI的敏感性为87.6%，对STEMI诊断的特异性为93.1%；S100A12可以作为STEMI发病早期诊断标志物预测AMI的发生。同时研究发现S100A12与STEMI心血管不良事件的发生存在相关关系。功能学研究发现1、S100A12及其受体RAGE在人冠状动脉粥样硬化斑块的巨噬细胞中大量表达，S100A12及其受体RAGE可能通过影响巨噬细胞炎症反应参与冠状动脉粥样硬化不稳定斑块的进程；2、动物学水平分析巨噬细胞特异性表达的S100A12转基因小鼠证明S100A12通过促进巨噬细胞炎症反应导致脉粥样硬化斑块的形成；Western diet喂养Lyz-S100A12/ApoE-/-和ApoE-/-小鼠16周后，两组小鼠的主动脉血管组织蛋白表达谱显示PDCD4在Lyz-S100A12/ApoE-/-组中明显升高，曲尼斯特通过拮抗S100A12与RAGE受体结合对动脉粥样硬化的发展起到抑制作用。3、细胞学水平实验进一步验证S100A12与RAGE受体结合后激活PDCD4的表达，进而引起下游NF-κB p65信号通路的激活，炎症因子的表达升高，导致动脉粥样硬化斑块的形成与发展。S100A12作为钙离子调节蛋白家族成员与RAGE受体结合后能够加速冠状动脉粥样硬化不稳定斑块形成和破裂，引起STEMI的发生，对S100A12展开研究机制探索有望为急性心肌梗死的精准治疗提高新的治疗靶点。