PCSK9Qβ-003 Vaccine Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice
PCSK9Qβ-003 Vaccine Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice
复制标题
PCSK9Qβ-003 疫苗可减轻载脂蛋白 E 缺陷小鼠的动脉粥样硬化
DOI：
10.1007/s10557-020-07041-6
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发表时间：
2020
影响因子：
3.4
通讯作者：
Zhihua Qiu
中科院分区：
文献类型：
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作者：
Danyu Wu;Yajie Pan;Shijun Yang;Chang Li;Yanzhao Zhou;Yingxuan Wang;Xiao Chen;Zihua Zhou;Yuhua Liao;Zhihua Qiu
目的本课题组研制了一种靶向枯草杆菌蛋白转化酶/可溶蛋白9型（PCSK9）的治疗性疫苗，命名为PCSK9Qβ-003。在这项研究中，我们研究了PCSK9Qβ-003疫苗对动脉粥样硬化的潜在有效性。方法将ApoE - / -小鼠随机分为磷酸缓冲盐水（PBS）组、Qβ病毒样颗粒（VLP）组和PCSK9Qβ-003疫苗组。PCSK9Qβ-003组小鼠注射PCSK9Qβ-003疫苗4次（100 μg/次），持续18周。研究了疫苗对动脉粥样硬化斑块、胆固醇转运、炎症和细胞凋亡的影响。结果PCSK9Qβ-003疫苗能明显降低ApoE−/−小鼠的总胆固醇和低密度脂蛋白胆固醇。与其他组相比，PCSK9Qβ-003疫苗显著减少了病变面积，促进了动脉粥样硬化斑块的稳定性。该疫苗通过上调肝脏X受体α和ATP结合盒转运体A1的表达水平，调节ApoE−/−小鼠主动脉中的胆固醇转运。此外，PCSK9Qβ-003疫苗可显著降低小鼠巨噬细胞浸润、单核细胞趋化蛋白-1和肿瘤坏死因子-α的表达。该疫苗还能显著减少ApoE−/−小鼠主动脉病变区域的细胞凋亡。结论PCSK9Qβ-003疫苗可通过调节胆固醇逆向转运、抑制炎症浸润和细胞凋亡等方式减缓动脉粥样硬化的进展，可能为动脉粥样硬化的治疗提供新的途径，并显著提高患者的治疗依从性。
PurposeOur group has developed a therapeutic vaccine targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), named PCSK9Qβ-003. In this study, we investigated the potential effectiveness of the PCSK9Qβ-003 vaccine on atherosclerosis.MethodsMale ApoE−/−mice were randomly assigned to three groups: a phosphate-buffered saline (PBS) group, Qβ virus-like particles (VLP) group, and PCSK9Qβ-003 vaccine group. Mice in the PCSK9Qβ-003 group were injected with the PCSK9Qβ-003 vaccine four times (100 μg/time) over a period of 18 weeks. The effects of the vaccine on atherosclerotic plaque, cholesterol transport, inflammation and apoptosis were investigated.ResultsThe PCSK9Qβ-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in ApoE−/−mice. Compared with the other groups, the PCSK9Qβ-003 vaccine significantly reduced the lesion area and promoted the stability of atherosclerotic plaque. The vaccine regulated cholesterol transport in the aorta of ApoE−/−mice by up-regulating the expression level of liver X receptor α and ATP binding cassette transporter A1. Additionally, macrophage infiltration and expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α were significantly decreased in the mice administered the PCSK9Qβ-003 vaccine. The vaccine also markedly reduced apoptosis in the lesion area of the aorta in ApoE−/−mice.ConclusionsThe results demonstrated that the PCSK9Qβ-003 vaccine attenuated the progression of atherosclerosis by modulating reverse cholesterol transport and inhibiting inflammation infiltration and apoptosis, which may provide a novel therapeutic approach for atherosclerosis and greatly improve treatment compliance among patients.