The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice.
The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice.
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DOI：
10.1093/eurheartj/ehx260
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发表时间：
2017-08-21
影响因子：
39.3
通讯作者：
Galabova G
中科院分区：
文献类型：
--
作者：
Landlinger C;Pouwer MG;Juno C;van der Hoorn JWA;Pieterman EJ;Jukema JW;Staffler G;Princen HMG;Galabova G
枯草杆菌前蛋白转换酶9(PCSK9)已成为治疗高胆固醇血症和动脉粥样硬化的有效靶点。PCSK9结合低密度脂蛋白受体并促进其降解，导致低密度脂蛋白胆固醇(LDLc)的清除减少，从而增加动脉粥样硬化的风险。在这项研究中，AT04A抗PCSK9疫苗在改善甚至预防致动脉粥样硬化的APOE*3Leden.CETP小鼠模型中的治疗潜力方面进行了评估。对照组和AT04A疫苗组小鼠以西式饲料喂养18 周。抗体滴度、血脂和炎症标志物分别用ELISA法、FPLC法和多重免疫测定法进行监测。通过对主动脉窦连续横切面的组织学分析，评估动脉粥样硬化的进展。AT04A疫苗诱导了针对PCSK9的高而持久的抗体水平，导致血浆总胆固醇(−53%，P <； 0.001)和低密度脂蛋白(LDLc)与对照组相比显著降低。血清淀粉样蛋白A、巨噬细胞炎性蛋白-1β、巨噬细胞源性趋化因子、细胞因子干细胞因子和血管内皮生长因子A等炎性标志物显著降低。结果，与对照组相比，AT04A疫苗治疗组动脉粥样硬化病变面积减少(−%，P = 0.004)，主动脉炎症反应减少(+119%，P = 0.026)，无病变主动脉节段增多(P<0.05)。AT04A疫苗可在APOE*3Leden.CETP小鼠体内诱导针对PCSK9的有效免疫反应，显著降低血脂、全身和血管炎症以及动脉粥样硬化病变。
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. 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. 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.
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影响因子：
24
作者：
Ference BA;Majeed F;Penumetcha R;Flack JM;Brook RD
通讯作者：
Brook RD
影响因子：
6.5
作者：
Kühnast S;van der Hoorn JW;Pieterman EJ;van den Hoek AM;Sasiela WJ;Gusarova V;Peyman A;Schäfer HL;Schwahn U;Jukema JW;Princen HM
通讯作者：
Princen HM
影响因子：
4.4
作者：
Abela, George S.
通讯作者：
Abela, George S.
影响因子：
6.5
作者：
Fattori, Elena;Cappelletti, Manuela;Monaci, Paolo
通讯作者：
Monaci, Paolo
影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J