title: Development of Accelerated Coronary Atherosclerosis Model Using Low Density Lipoprotein Receptor Knock-Out Swine with Balloon Injury.
abstract: BACKGROUND
  Several animal models have facilitated the evaluation and pathological understanding of atherosclerosis, but a definitive animal model of coronary atherosclerosis is not available. We therefore developed low density lipoprotein receptor knockout (LDLR-KO) pigs with hypercholesterolemia, a model which rapidly developed coronary atherosclerosis following balloon injury.
  
  
  RESULTS
  We deleted LDLR exon regions from cultured porcine fetal fibroblasts and cloned LDLR knockout (LDLR-KO) embryos microinjecting fetal fibroblast nuclei into enucleated oocytes. Twelve LDLR-KO pigs were fed a 2.0% cholesterol and 20% fat diet. Baseline serum LDL cholesterol level was 510.0±86.1 mg/dL. Balloon injury was created in 46 coronary segments and necropsy were obtained 2, 4, 8 and 12 weeks later. Coronary artery sections were reviewed to evaluate lesion progression. We found lipid accumulation with foam cells and inflammatory cells beginning four weeks after balloon injury. The mean ratio of macrophages to plaque area was significantly higher in the four- weeks and eight-week animals compared with those at 2-weeks (8.79% ± 5.98% and 17.00% ± 10.38% vs. 1.14% ± 1.88%, P < 0.0001). At 12 weeks the ratio decreased toward the level at 2 week level (4.00% ± 4.56%, P = 0.66 vs. baseline). Advanced coronary atherosclerotic lesions contained lipid pools at eight-weeks with fibrous components beginning at 12 weeks.
  
  
  CONCLUSIONS
  We developed a model of rapid coronary atherosclerosis using LDLR KO pigs with balloon injury. This model may be useful for preclinical evaluation of medication or devices, and may also help investigate mechanisms of plaque progression.
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ogita
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Miyauchi
authors.affiliation: Transgenic Animal Research Center, National Institute of Agrobiological Sciences, Tsukuba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Onishi
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shuta
authors.initials: S
authors.lastname: Tsuboi
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Naito
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Dohi
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kasai
authors.affiliation: Division of Biomedical Imaging Research, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Minneapolis Heart Institute and Foundation, Minneapolis, Minnesota, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Schwartz
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000473:pathology*; D055785:Gene Knockdown Techniques; D011973:Receptors, LDL / Q000235:genetics*; D013552:Swine
chemical_list: D011973:Receptors, LDL