Abstract Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model. Methods and results Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (−53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1β (MIP-1β/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (−64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control. Conclusions AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta.

中文翻译：

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针对前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型的 AT04A 疫苗可降低 APOE*3Leiden.CETP 小鼠的总胆固醇、血管炎症和动脉粥样硬化

摘要 目的 前蛋白转化酶枯草杆菌蛋白酶 / kexin 9 型 (PCSK9) 已成为治疗高胆固醇血症和动脉粥样硬化的有希望的治疗靶点。PCSK9与低密度脂蛋白受体结合并增强其降解，导致低密度脂蛋白胆固醇（LDLc）的清除率降低，动脉粥样硬化的风险增加。在这项研究中，评估了 AT04A 抗 PCSK9 疫苗在致动脉粥样硬化性 APOE*3Leiden.CETP 小鼠模型中改善甚至预防冠心病的治疗潜力。方法和结果 对照组和AT04A疫苗处理的小鼠喂食西式饮食18周。分别通过 ELISA、FPLC 和多重免疫测定法监测抗体滴度、血浆脂质和炎症标志物。通过对主动脉窦连续横截面的组织学分析评估动脉粥样硬化的进展。与对照相比，AT04A 疫苗诱导了针对 PCSK9 的高且持久的抗体水平，导致血浆总胆固醇（-53%，P < 0.001）和 LDLc 显着降低。血浆炎症标志物，如血清淀粉样蛋白 A (SAA)、巨噬细胞炎症蛋白-1β (MIP-1β/CCL4)、巨噬细胞衍生趋化因子 (MDC/CCL22)、细胞因子干细胞因子 (SCF) 和血管内皮生长因子 A。 VEGF-A) 在 AT04A 处理的小鼠中显着减少。因此，与 AT04A 疫苗治疗相比，动脉粥样硬化病变面积（-64%，P = 0.004）和主动脉炎症以及更多无病变主动脉节段（+119%，P = 0.026）减少与控制。