Abstract
Background: Intestinal cholesterol absorption inhibitor ezetimibe added to statin therapy has recently demonstrated clinical benefits in the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial trial by further reducing Low Density Lipoprotein-Cholesterol (LDL-C) levels than statin therapy alone. Here we investigated the mechanisms by which inhibition of intestinal cholesterol absorption could contribute to the clinically observed cardiovascular events reduction by evaluating its effect on inflammatory plaque development in apolipoprotein E-/- (ApoE-/-) mice. Methods: ApoE-/- mice were fed a Paigen diet (1.25% cholesterol, 0.5% cholic acid and 15% fat) without or with ezetimibe (7 mg/kg/day) for 6 weeks. A first set of mice (n = 15) was used to assay the effects of ezetimibe on LDL-C by injecting intravenously 3H-cholesteryl oleate labeled human LDL and a second set (n = 20) was used to evaluate the expression of the inflammatory marker Vascular Cell Adhesion Molecule-1 (VCAM-1) in atherosclerotic plaques using the imaging agent 99mTc-cAbVCAM1-5. A third set of mice (n = 21) was used to compare VCAM-1 expression and 99mTc-cAbVCAM1-5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL-cholesteryl ester plasma disappearance rate (p<0.001 vs. control) after 3H-cholesteryl oleate labeled LDL injection. At time 96 hours after injection, hepatic fraction of 3H-tracer was 61% lower in mice treated with ezetimibe (p<0.001). Meanwhile, LDL-derived 3H-cholesterol excretion in the feces was 107% higher (p<0.001). The anti-atherogenic effect of ezetimibe monitored by 99mTc-cAbVCAM1-5 Single Photon Emission Computed Tomography (SPECT) imaging showed a 49% reduction in aortic tracer uptake (0.95 ± 0.04 vs. 1.87 ± 0.11 %ID/cm3, P<0.01). In addition to hypercholesterolemia, the pro-inflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues including the aorta and this expression was highly correlated with 99mTc-cAbVCAM1-5 uptake (r = 0.75; P<0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes anti-atherosclerotic effects through increased LDL-C catabolism and LDL-derived cholesterol fecal excretion, and reduces inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding ezetimibe to a statin therapy.
- Animal Imaging
- Cardiology (basic/technical)
- SPECT/CT
- 99mTc-cAbVCAM1-5
- Atherosclerosis
- Ezetimibe
- LDL-cholesterol
- VCAM-1
- Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.