Abstract 14060: The Influence on Plaque Formation and Endothelial Function in Apoe-Deficient Mice by Direct Thrombin Inhibition with Dabigatran
Background: Recently developed oral anticoagulants directly inhibit thrombin (dabigatran). In this study we investigated the effects of direct thrombin inhibition on atherosclerosis and endothelial function in a hypercholesterolemic mouse model with accelerated atherosclerosis (ApoE-/--mice).
Methods: ApoE-/- mice were treated with a cholesterol-rich diet for 12 weeks and dabigatran (900mg/kg body weight) or placebo. Wildtype (WT, C57/B6) mice served as control. Endothelial function of aortic rings was assessed by pharmacological stimulation with carbachol (endothelium-dependent) using glyceroltrinitrate (endothelium-independent) as control. Atherosclerotic lesion formation was evaluated with oil-red staining and vascular collagen content was determined by Sirius red staining. Modulation of reactive oxygen species (ROS) production was determined by semiquantitative immunohistochemical staining.
Results: Treatment with dabigatran attenuated atherosclerotic plaque formation (ApoE-/--Dabi: 16.1±3.8% of ApoE-/--control, p<0.001), decreased collagen content (ApoE-/--Dabi: 49.1±10% of ApoE-/--control, p=0.01) and ROS production in DHE-staining (ApoE-/--Dabi: 50.7±4.1% of ApoE-/--control, p=0.014) in parallel to an improvement of endothelial function (ApoE-/--control42.6±2.7 vs. ApoE-/--Dabi 62.9±3.3% of phenylephrine-induced contraction, p=0.001) at 100 µM carbachol.
Conclusion: Direct thrombin inhibition improved endothelial function, and reduced atherosclerotic lesion size, vascular collagen content and oxidative stress in hypercholesterolemic atherosclerosis. Interference with the coagulation system might provide a therapeutic means to modify atherosclerotic disease progression.
- © 2012 by American Heart Association, Inc.