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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 E2/2 mice. Methods: Apolipoprotein E2/2 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 5 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 5 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 5 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 , 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 , 0.001). Meanwhile, LDL-derived 3H-cholesterol excretion in the feces was 107% higher (P , 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 6 0.04 vs. 1.87 6 0.11; P , 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 5 0.75; P , 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.

International audience; Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make it a potential peptide of choice for clinical and biotechnological applications. The aim of the present study was to gain new information about the properties of MCa in vivo in order to delineate the future potential applications of this vector. For this purpose, two analogues of this peptide with (Tyr-MCa) and without (Lin-Tyr-MCa) disulfide bridges were synthesized, radiolabeled with (125)I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that (125)I-Tyr-MCa was stable in vitro and that the disulfide bridges conferred a competitive advantage for the stability of peptide. Following in vivo injection in mice, (125)I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal.

International audience; 99mTc-cAbVCAM1-5 is a single-domain antibody fragment (sd-Ab) directed against mouse/human Vascular Cell Adhesion Molecule 1 (VCAM-1) which has recently been proposed as a new imaging agent for the detection of inflamed atherosclerotic lesions. Indeed, in a mouse model of atherosclerosis, 99mTc-cAbVCAM1-5 specifically bound to VCAM-1 positive lesions, thereby allowing their identification on SPECT images. The purpose of the present study was to investigate 99mTc-cAbVCAM1-5 imaging sensitivity using a reference statin therapy.Methods. Thirty ApoE-deficient mice were fed a western-type diet. First, the relationship between the level of VCAM-1 expression and 99mTc-cAbVCAM1-5 uptake was evaluated in 18 mice using immunohistochemistry and autoradiography (ARG). Second, longitudinal SPECT/CT imaging was performed on control (n=9) or atorvastatin-treated mice (0.01% w/w, n=9).Results. 99mTc-cAbVCAM1-5 uptake in atherosclerotic lesions correlated with the level of VCAM-1 expression (P

International audience; 99mTc-cAbVCAM1-5 is a single-domain antibody fragment (sd-Ab) directed against mouse/human Vascular Cell Adhesion Molecule 1 (VCAM-1) which has recently been proposed as a new imaging agent for the detection of inflamed atherosclerotic lesions. Indeed, in a mouse model of atherosclerosis, 99mTc-cAbVCAM1-5 specifically bound to VCAM-1 positive lesions, thereby allowing their identification on SPECT images. The purpose of the present study was to investigate 99mTc-cAbVCAM1-5 imaging sensitivity using a reference statin therapy.Methods. Thirty ApoE-deficient mice were fed a western-type diet. First, the relationship between the level of VCAM-1 expression and 99mTc-cAbVCAM1-5 uptake was evaluated in 18 mice using immunohistochemistry and autoradiography (ARG). Second, longitudinal SPECT/CT imaging was performed on control (n=9) or atorvastatin-treated mice (0.01% w/w, n=9).Results. 99mTc-cAbVCAM1-5 uptake in atherosclerotic lesions correlated with the level of VCAM-1 expression (P