Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse - Model characterization and effects of pravastatin treatment

被引:219
作者
Johnson, J [1 ]
Carson, K [1 ]
Williams, H [1 ]
Karanam, S [1 ]
Newby, A [1 ]
Angelini, G [1 ]
George, S [1 ]
Jackson, C [1 ]
机构
[1] Univ Bristol, Bristol Royal Infirm, Bristol Heart Inst, Bristol BS2 8HW, Avon, England
关键词
atherosclerosis; plaque; pathology; drugs;
D O I
10.1161/01.CIR.0000158435.98035.8D
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. Methods and 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.
引用
收藏
页码:1422 / 1430
页数:9
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