Plaque Rupture After Short Periods of Fat Feeding in the Apolipoprotein E–Knockout Mouse

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. 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 1.05Ϯ0.15 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 16Ϯ4 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% (PϽ0.0001). In longer-term experiments, the delay of pravastatin treatment until unstable plaques had developed reduced the incidence of acute plaque rupture by 36% (PϽ0.0001). 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.

Statins Induce the Accumulation of Regulatory T Cells in Atherosclerotic Plaque

“…Therefore, the result shows that simvastatin promote an accumulation of Tregs within the atherosclerotic plaques. Interestingly, we did not find a significant difference in serum levels of total cholesterol, triglycerides and LDL cholesterol with and without sim- vastatin in ApoE -/-mice, which was consistent with the previous studies (27,28), indicating that simvastatin influenced the number of Tregs in plaques, independent of its lipid-lowering properties. Tregs secrete two major cytokines (TGF-β and IL-10), which are associated with their survival and function (30).…”

“…However, no study has investigated the effect of statins on Tregs in atherosclerotic plaques. As well known, atherosclerotic lesions can develop in ApoE -/-mice throughout the arterial tree and such mice are thought to be a wellestablished genetic animal model of atherosclerosis, with many morphologic characteristics resembling that in humans (28). Therefore, in this study, we induced atherosclerotic plaque in ApoE -/-mice by placing a silastic perivascular collar around the right common carotid artery and introducing a lipid-rich diet (20,21).…”

Comparison of 99mTc-annexin A5 with 18F-FDG for the detection of atherosclerosis in ApoE−/− mice

“…We used ApoE-/-mice, a type of spontaneous atherosclerosis animal model, which develop atherosclerotic lesions slowly in its aortic tissues throughout the whole arterial tree. Several publications have been issued recently which demonstrated the vulnerability of plaques in apoE-/-mice, especially in the high-fat feeding apoE-/-mice [26][27][28][29]. Intramural bleeding was also reportedly observed in the brachiocephalic arteries at an older age (60 weeks old) possibly caused by plaque rupture [43].…”

“…Recently, some investigators have also observed spontaneous plaque rupture in the brachiocephalic arteries and subsequent sudden death in aged ApoE-/-mice [26][27][28][29]. These data suggest that ApoE-/-mice could be a useful model for the evaluation of tracers for detecting unstable atherosclerotic lesions.…”

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

“…Compared to rodents, human plaques show more complex lesions and specifically more calcification. Experimental characterization of plaque instability is challenging as mouse models for atherosclerotic plaque rupture are scarcely available [44][45][46] and not well characterized [47].…”