title: A Translational Model for Diet-related Atherosclerosis: Effect of Statins on Hypercholesterolemia and Atherosclerosis in a Minipig.
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.
authors.affiliation: MPI Research, Mattawan, Michigan, USA dozie.amuzie@gmail.com.
authors.forename: Chidozie
authors.initials: C
authors.lastname: Amuzie
authors.affiliation: Exemplar Genetics, Sioux Center, Iowa, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Swart
authors.affiliation: Exemplar Genetics, Sioux Center, Iowa, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Rogers
authors.affiliation: MPI Research, Mattawan, Michigan, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vihtelic
authors.affiliation: MPI Research, Mattawan, Michigan, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Denham
authors.affiliation: MPI Research, Mattawan, Michigan, USA.
authors.forename: Dale E
authors.initials: DE
authors.lastname: Mais
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D050197:Atherosclerosis; D000069059:Atorvastatin / Q000494:pharmacology / Q000627:therapeutic use; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics*; D013552:Swine; D013556:Swine, Miniature; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D000069059:Atorvastatin
keywords: atherosclerosis; hypercholesterolemia; minipig; translational model