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Toxicol Pathol ; 44(3): 442-9, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26883155

ABSTRACT

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.


Subject(s)
Disease Models, Animal , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Receptors, LDL/genetics , Translational Research, Biomedical/methods , Animals , Animals, Genetically Modified , Aorta/drug effects , Aorta/pathology , Atherosclerosis , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Diet, High-Fat , Femoral Artery/drug effects , Femoral Artery/pathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/drug therapy , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Swine , Swine, Miniature
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