Amuzie Chidozie, Swart John R, Rogers Christopher S, Vihtelic Thomas, Denham Steven, Mais Dale E
MPI Research, Mattawan, Michigan, USA
Exemplar Genetics, Sioux Center, Iowa, USA.
Toxicol Pathol. 2016 Apr;44(3):442-9. doi: 10.1177/0192623315622304. Epub 2016 Feb 16.
Models of atherosclerosis are used in preclinical studies but often fail to translate to humans. A model that better reflects human atherosclerosis is necessary. We recently engineered the ExeGen™ low-density lipoprotein receptor (LDLR) miniswine, in which the LDL receptor gene is modified to drive hypercholesterolemia and atherosclerosis, and showed diet-related exacerbation of these phenotypes. Five groups of animals, either wild type (+/+) or heterozygous (+/-), were fed either a normal or high-fat diet for 6 months. One group of heterozygous pigs fed a high-fat diet was also administered atorvastatin at 3 mg/kg/day. Clinical chemistry and anatomic pathology parameters were measured biweekly and at termination. The high-fat diet resulted in increased adiposity and interspersion of adipocytes within the salivary glands. The heterozygous pigs on the high-fat diet gained more weight and had significant increases in total cholesterol, high-density lipoprotein, and LDL compared to wild-type animals or heterozygous animals fed a normal diet. Atorvastatin attenuated these parameters, indicating the statin had a beneficial effect, even in a high-fat diet scenario. Atorvastatin treatment also reduced the intensity of Oil Red O staining in pigs on high-fat diet. Atorvastatin-related amelioration of several indices of cardiovascular pathophysiology in this model underscores its utility for drug discovery.
动脉粥样硬化模型用于临床前研究，但往往无法转化应用于人类。因此需要一种能更好反映人类动脉粥样硬化的模型。我们最近构建了ExeGen™低密度脂蛋白受体（LDLR）小型猪，其中低密度脂蛋白受体基因经过修饰，可引发高胆固醇血症和动脉粥样硬化，并显示出这些表型与饮食相关的恶化情况。将五组动物，分为野生型（+/+）或杂合子（+/-），分别给予正常饮食或高脂饮食6个月。其中一组高脂饮食的杂合子猪还按3毫克/千克/天的剂量给予阿托伐他汀。每两周及实验结束时测量临床化学和解剖病理学参数。高脂饮食导致脂肪增多，且脂肪细胞散布于唾液腺内。与野生型动物或正常饮食的杂合子动物相比，高脂饮食的杂合子猪体重增加更多，总胆固醇、高密度脂蛋白和低密度脂蛋白显著升高。阿托伐他汀使这些参数有所改善，表明他汀类药物即使在高脂饮食情况下也具有有益作用。阿托伐他汀治疗还降低了高脂饮食猪的油红O染色强度。该模型中阿托伐他汀对心血管病理生理学多个指标的改善作用突出了其在药物研发中的效用。
