小鼠动脉粥样硬化模型是研究动脉粥样硬化病理生理学和药物开发的关键。然而，它们并不以自发性动脉粥样硬化血栓形成为动脉粥样硬化的最后阶段。表达人类突变载脂蛋白 E 形成APOE*3-Leiden和人类胆固醇酯转移蛋白 ( CETP ) 的转基因小鼠，即APOE*3-Leiden.CETP小鼠，具有中度高脂蛋白血症和动脉粥样硬化表型。与载脂蛋白 E 缺陷 ( Apoeˉ / ˉ ) 小鼠相比，APOE*3-Leiden.CETP小鼠对降脂和抗动脉粥样硬化药物反应良好。该研究的目的是调查是否抗凝蛋白 C 的沉默（Proc ) 允许APOE*3-Leiden.CETP小鼠将血栓形成作为动脉粥样硬化的最后阶段。给雌性APOE*3-Leiden.CETP小鼠喂食西式饮食以诱导晚期动脉粥样硬化，然后注射靶向Proc (si Proc ) 的小干扰 RNA。通过主动脉根部的组织学分析确定动脉粥样硬化和动脉血栓形成的存在。APOE*3-Leiden.CETP小鼠主动脉根部的动脉粥样硬化严重程度从“0”型（无病变）到“V”型病变（晚期和复杂病变）不等。21 个APOE*3-Leiden.CETP中的 4 个观察到si Proc注射后的动脉粥样硬化血栓形成小鼠（发生率 19%）。动脉粥样硬化血栓形成在主动脉根部的晚期（“V”型）动脉粥样硬化斑块之上表现为大的、有组织的、富含纤维蛋白和白细胞的血栓。这种动脉粥样硬化血栓形成的外观和发病率与先前报道的具有更严重动脉粥样硬化的Apoeˉ / ˉ小鼠（发生率 19%）相当。具有中度高脂血症和动脉粥样硬化的APOE*3-Leiden.CETP小鼠可在短暂的Proc沉默后发展为动脉粥样硬化血栓形成。这进一步扩大了这些小鼠作为降脂和抗动脉粥样硬化药物试验模型的用途。
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Atherothrombosis model by silencing of protein C in APOE*3-Leiden.CETP transgenic mice
Murine atherosclerosis models are key for investigation of atherosclerosis pathophysiology and drug development. However, they do not feature spontaneous atherothrombosis as a final stage of atherosclerosis. Transgenic mice expressing both the human mutant apolipoprotein E form APOE*3-Leiden and human cholesteryl ester transfer protein (CETP), i.e. APOE*3-Leiden.CETP mice, feature a moderate hyperlipoproteinemia and atherosclerosis phenotype. In contrast to apolipoprotein E deficient (Apoeˉ/ˉ) mice, APOE*3-Leiden.CETP mice respond well to lipid-lowering and anti-atherosclerotic drugs. The aim of the study was to investigate whether silencing of anticoagulant Protein C (Proc) allows APOE*3-Leiden.CETP mice to feature thrombosis as a final stage of atherosclerosis. Female APOE*3-Leiden.CETP mice were fed a Western-type diet to induce advanced atherosclerosis, followed by an injection with a small interfering RNA targeting Proc (siProc). Presence of atherosclerosis and atherothrombosis was determined by histologic analysis of the aortic root. Atherosclerosis severity in the aortic root area of APOE*3-Leiden.CETP mice varied from type “0” (no lesions) to type “V” lesions (advanced and complex lesions). Atherothrombosis following siProc injection was observed for 4 out of 21 APOE*3-Leiden.CETP mice (19% incidence). The atherothrombosis presented as large, organized, fibrin- and leukocyte-rich thrombi on top of advanced (type “V”) atherosclerotic plaques in the aortic root. This atherothrombosis was comparable in appearance and incidence as previously reported for Apoeˉ/ˉ mice with a more severe atherosclerosis (19% incidence). APOE*3-Leiden.CETP mice with modest hyperlipidemia and atherosclerosis can develop atherothrombosis upon transient Proc-silencing. This further extends the use of these mice as a test model for lipid-lowering and anti-atherosclerotic drugs.