RT Journal Article
SR Electronic
T1 Evaluation of Antiatherogenic Properties of Ezetimibe Using <sup>3</sup>H-Labeled Low-Density-Lipoprotein Cholesterol and <sup>99m</sup>Tc-cAbVCAM1–5 SPECT in ApoE<sup>−/−</sup> Mice Fed the Paigen Diet
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1088
OP 1093
DO 10.2967/jnumed.116.177279
VO 58
IS 7
A1 Laurent S. Dumas
A1 François Briand
A1 Romain Clerc
A1 Emmanuel Brousseau
A1 Christopher Montemagno
A1 Mitra Ahmadi
A1 Sandrine Bacot
A1 Audrey Soubies
A1 Pascale Perret
A1 Laurent M. Riou
A1 Nick Devoogdt
A1 Tony Lahoutte
A1 Gilles Barone-Rochette
A1 Daniel Fagret
A1 Catherine Ghezzi
A1 Thierry Sulpice
A1 Alexis Broisat
YR 2017
UL http://jnm.snmjournals.org/content/58/7/1088.abstract
AB The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E−/− mice. Methods: Apolipoprotein E−/− mice were fed the Paigen diet (1.25% cholesterol, 0.5% cholic acid, and 15% fat) without or with ezetimibe (7 mg/kg/d) for 6 wk. In a first set of mice (n = 15), we intravenously injected 3H-cholesteryl oleate–labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set (n = 20), we used the imaging agent 99mTc-cAbVCAM1–5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set (n = 21), we compared VCAM-1 expression with 99mTc-cAbVCAM1–5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL–cholesteryl ester plasma disappearance rate (P &lt; 0.001 vs. control) after 3H-cholesteryl oleate–labeled LDL injection. At 96 h after injection, the hepatic fraction of 3H-tracer was 61% lower in mice treated with ezetimibe (P &lt; 0.001). Meanwhile, LDL-derived 3H-cholesterol excretion in the feces was 107% higher (P &lt; 0.001). The antiatherogenic effect of ezetimibe monitored by 99mTc-cAbVCAM1–5 SPECT showed a 49% reduction in aortic tracer uptake (percentage injected dose per cubic centimeter, 0.95 ± 0.04 vs. 1.87 ± 0.11; P &lt; 0.01). In addition to hypercholesterolemia, the proinflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues, including the aorta, and this expression correlated strongly with 99mTc-cAbVCAM1–5 uptake (r = 0.75; P &lt; 0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes antiatherosclerotic effects through increased LDL cholesterol 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.