Abstract：
Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor (LDLR) and mediates its internalization and degradation, resulting in an increase in LDL cholesterol levels. Recently, PCSK9 emerged as a therapeutic target for hypercholesterolemia and atherosclerosis. In this study, we develop a PCSK9 nanoparticle (NP) vaccine by covalently conjugating the catalytic domain (aa 153-aa 454, D374Y) of PCSK9 to self-assembled 24-mer ferritin NPs. We demonstrate that the PCSK9 NP vaccine effectively induces interfering antibodies against PCSK9 and reduces serum lipids levels in both a high-fat diet-induced hypercholesterolemia model and an adeno-associated virus-hPCSK9D374Y-induced hypercholesterolemia model. Additionally, the vaccine significantly reduces plaque lesion areas in the aorta and macrophages infiltration in an atherosclerosis mouse model. Furthermore, we discover that the vaccine\'s efficacy relied on T follicular help cells and LDLR. Overall, these findings suggest that the PCSK9 NP vaccine holds promise as an effective treatment for hypercholesterolemia and atherosclerosis.
摘要：
前蛋白转化酶枯草杆菌蛋白酶/kexin9型（PCSK9）与低密度脂蛋白受体（LDLR）结合并介导其内化和降解，导致LDL胆固醇水平升高。最近,PCSK9成为高胆固醇血症和动脉粥样硬化的治疗靶点。在这项研究中,我们通过将PCSK9的催化域（aa153-aa454，D374Y）与自组装的24聚体铁蛋白NP共价缀合来开发PCSK9纳米颗粒（NP）疫苗。我们证明了PCSK9NP疫苗在高脂饮食诱导的高胆固醇血症模型和腺相关病毒-hPCSK9D374Y诱导的高胆固醇血症模型中有效诱导针对PCSK9的干扰抗体并降低血清脂质水平。此外,在动脉粥样硬化小鼠模型中，该疫苗显著减少了主动脉中的斑块病变区域和巨噬细胞浸润。此外，我们发现疫苗的功效依赖于T滤泡辅助细胞和LDLR。总的来说,这些研究结果表明,PCSK9NP疫苗有望成为治疗高胆固醇血症和动脉粥样硬化的有效药物.
