Familial Hypercholesterolemia and Atherosclerosis in Cloned Minipigs Created by DNA Transposition of a Human PCSK9 Gain-of-Function Mutant
Familial Hypercholesterolemia and Atherosclerosis in Cloned Minipigs Created by DNA Transposition of a Human PCSK9 Gain-of-Function Mutant
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DOI：
10.1126/scitranslmed.3004853
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发表时间：
2013-01-02
影响因子：
17.1
通讯作者：
Bentzon, Jacob F.
中科院分区：
文献类型：
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作者：
Al-Mashhadi, Rozh H.;Sorensen, Charlotte B.;Bentzon, Jacob F.
缺乏与人类相似大小和病理学的动物模型阻碍了动脉粥样硬化的转化研究。小鼠模型缺少人类动脉粥样硬化的中心特征，并且对于血管内程序和成像来说太小。在小型猪中建立这种疾病的模型可以克服这些局限性，但是已经证明，仅通过高脂肪喂养很难在正常猪中诱导快速动脉粥样硬化，并且没有类似于在小鼠中创建的基因修饰模型。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）基因中的D374 Y功能获得性突变导致严重的常染色体显性高胆固醇血症并加速人类动脉粥样硬化。使用睡美人DNA转座和体细胞核移植克隆，我们创建了具有肝脏特异性表达人D374 Y-PCSK 9的尤卡坦小型猪。D374 Y-PCSK 9转基因猪显示肝脏低密度脂蛋白（LDL）受体水平降低、LDL清除受损、重度高胆固醇血症和自发发展的进行性动脉粥样硬化病变（可通过非侵入性成像观察到）。这个模型应该证明是有用的几种类型的动脉粥样硬化的转化研究。
Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.