Evaluation of anti-atherogenic effects of P2Y12 receptor antagonists in Apolipoprotein E-deficient mice

Abstract

Prasugrel and Ticagrelor, two P2Y12 receptors antagonists commonly used for the treatment of acute coronary syndrome, are suspected to exert anti-inflammatory effects, which may decrease atherosclerotic lesions. Moreover, Ticagrelor, through its interaction with adenosine metabolism, may have supplemental positive effect on inflammation and atherosclerosis. We evaluated in this study the effects of these two molecules on atherosclerotic lesions and inflammation on a murine model of atherosclerosis. Firstly, twelve C57BL/6 mice treated by vehicule ( N = 4), Prasugrel ( N = 4) or Ticagrelor ( N = 4) were used to evaluate the comparability of the anti-platelet effects by aggregometry. Then, twenty-one Apolipoprotein E deficient mice (ApoE -/-) fed a paigen diet (1.25% cholesterol, 0.5% cholic acid, 15% fat) were treated with vehicule ( N = 7), Prasugrel 5 mg/kg/day ( N = 7), or Ticagrelor 180 mg/kg/day ( N = 7) during 6 weeks. Anti-atherosclerotic effects of these molecules were evaluated in vivo using 99mTc-cAbVCAM1-5, an imaging agent evaluating the expression of the inflammatory marker Vascular Cell Adhesion Molecule-1 (VCAM-1). Maximum platelet aggregation was lower in C57BL/6 mice treated by Prasugrel and Ticagrelor (8%), than in mice treated by vehicule (70%). 99mTc-cAbVCAM1-5 uptake in the aortic root evaluated by in vivo Single Photon Emission Computed Tomography (SPECT) imaging (2.1 ± 0.6%ID/mm 3 vs 2.2 ± 0.7ID/mm 3 vs 1.9 ± 0.7ID/mm 3 ), ex-vivo biodistribution (2.9 ± 0.8%ID/g vs 2.5 ± 0.4%ID/g vs 2.6 ± 0.5%ID/g), and autoradiography (3.9 ± 1.0%ID/g vs 4.2 ± 1.0%ID/g vs 4.0 ± 0.6%ID/g) were not different between the control group, Prasugrel group and Ticagrelor group respectively. Ex vivo analysis confirmed that plaque surface and lipid content were identical between the three groups. Neither Prasugrel nor Ticagrelor has anti-atherosclerotic effects in this specific model of ApoE -/- mice fed a Paigen diet.