Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China; Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
Cell Rep Med. 2024 Jun 18;5(6):101614. doi: 10.1016/j.xcrm.2024.101614.
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-hPCSK9-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.
前蛋白转化酶枯草溶菌素 9（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 已成为治疗高胆固醇血症和动脉粥样硬化的靶点。在这项研究中，我们通过将 PCSK9 的催化结构域（aa153-aa454，D374Y）共价偶联到自组装的 24 聚体铁蛋白 NP 上来开发 PCSK9 纳米颗粒（NP）疫苗。我们证明，PCSK9 NP 疫苗可有效诱导针对 PCSK9 的干扰抗体，并降低高脂饮食诱导的高胆固醇血症模型和腺相关病毒-hPCSK9 诱导的高胆固醇血症模型中的血清脂质水平。此外，该疫苗可显著降低动脉粥样硬化小鼠模型中的主动脉斑块病变面积和巨噬细胞浸润。此外，我们发现该疫苗的疗效依赖于滤泡辅助 T 细胞和 LDLR。总之，这些发现表明 PCSK9 NP 疫苗有望成为治疗高胆固醇血症和动脉粥样硬化的有效方法。
