PCSK9通过调节肝脏脂质代谢仅能部分解释其与As的关系。推测其原因在于PCSK9除降脂外，有可能直接作用血管壁导致As，但有待进一步证实。申请者前期研究发现PCSK9与As发生的重要细胞巨噬细胞泡沫化及CD36表达有关。结合已有文献证据，申请者提出研究假说：PCSK9通过上调巨噬细胞CD36的表达，进而调控CD36所介导的信号通路，影响巨噬细胞泡沫化，直接促进As。本课题拟首先建立PCSK9过表达和干扰ApoE-/-小鼠As模型，明确PCSK9是否直接促进As；其次采用信号通路分级干预策略进一步探讨PCSK9是否通过CD36介导的信号通路促进巨噬细胞泡沫化，以揭示PCSK9通过CD36调控巨噬细胞功能促进As的分子机制。

PCSK9 regulating liver lipid metabolism is only partly to explain its relationship with As. The reason is speculated that PCSK9 may have a direct role to induce atherosclerosis in the vascular wall in addition to lipid-lowering, but which needs to be confirmed further. Applicant previous study found that PCSK9 is related with macrophage-derived foam cell formation and CD36 expression. Combined with the existing evidence from literatures, applicant propose scientific hypothesis as follows:PCSK9 promote atherosclerosis directly through affect macrophage-derived foam cells formation , which is achieved by upregulating the expression of CD36 and then regulating CD36-mediated signaling pathways. The project intends to first establish PCSK9 overexpression and interference ApoE-/ - mice atherosclerotic model, to define whether PCSK9 contributes to atherosclerosis directly; Second, signal molecular is intervented one by one to further explore whether PCSK9 promotes macrophage-derived foam cells formation through the signal pathway mediated by CD36, and to reveal the molecular mechanism of PCSK9 promotes atherosclerosis through CD36 to regulate macrophage function.