title: Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse: model characterization and effects of pravastatin treatment.
abstract: BACKGROUND
  These studies examined the early time course of plaque development and destabilization in the brachiocephalic artery of the apolipoprotein E-knockout mouse, the effects of pravastatin thereon, and the effects of pravastatin on established unstable plaques.
  
  
  RESULTS
  Male apolipoprotein E-knockout mice were fed a high-fat, cholesterol-enriched diet from the age of 8 weeks. Animals were euthanized at 1-week intervals between 4 and 9 weeks of fat feeding. Acutely ruptured plaques were observed in the brachiocephalic arteries of 3% of animals up to and including 7 weeks of fat feeding but in 62% of animals after 8 weeks, which suggests that there is a sharp increase in the number of plaque ruptures at 8 weeks. These acute plaque ruptures then appear to heal and form buried fibrous caps; after 9 weeks of fat feeding, mice had 1.05+/-0.15 buried fibrous caps at a single site in the brachiocephalic artery. Pravastatin (40 mg/kg of body weight per day for 9 weeks; resultant plasma concentration 16+/-4 nmol/L) had no effect on plasma cholesterol concentration in fat-fed apolipoprotein E-knockout mice but reduced the number of buried fibrous caps by 43% (P<0.0001). In longer-term experiments, the delay of pravastatin treatment until unstable plaques had developed reduced the incidence of acute plaque rupture by 36% (P<0.0001).
  
  
  CONCLUSIONS
  Plaque rupture occurs at high frequency in the brachiocephalic arteries of male apolipoprotein E-knockout mice after 8 weeks of fat feeding. Pravastatin treatment inhibits early plaque rupture and is also effective when begun after unstable plaques have developed.
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Johnson
authors.forename: Kevin
authors.initials: K
authors.lastname: Carson
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.forename: Sharada
authors.initials: S
authors.lastname: Karanam
authors.forename: Andrew
authors.initials: A
authors.lastname: Newby
authors.forename: Gianni
authors.initials: G
authors.lastname: Angelini
authors.forename: Sarah
authors.initials: S
authors.lastname: George
authors.forename: Christopher
authors.initials: C
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D016122:Brachiocephalic Trunk / Q000473:pathology*; D002791:Cholesterol, Dietary / Q000633:toxicity; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications* / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017035:Pravastatin / Q000627:therapeutic use*; D012422:Rupture, Spontaneous
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D017035:Pravastatin