A Translational Model for Diet-related Atherosclerosis: Effect of Statins on Hypercholesterolemia and Atherosclerosis in a Minipig

Toxicol Pathol. 2016 Apr;44(3):442-9. doi: 10.1177/0192623315622304. Epub 2016 Feb 16.

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.

Keywords: atherosclerosis; hypercholesterolemia; minipig; translational model.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Aorta / drug effects
  • Aorta / pathology
  • Atherosclerosis
  • Atorvastatin / pharmacology
  • Atorvastatin / therapeutic use
  • Diet, High-Fat
  • Disease Models, Animal*
  • 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
  • Receptors, LDL / genetics*
  • Swine
  • Swine, Miniature
  • Translational Medical Research / methods*

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Receptors, LDL
  • Atorvastatin