Abstract 19384: Direct Thrombin Inhibition by Dabigatran Protects against Severe Atherosclerosis Progression in Prothrombotic Mice
Introduction: Thrombin (FIIa) plays a key role in thrombus formation. Increased FIIa levels may also influence the onset and progression of atherosclerosis by inducing diverse cellular functions related to inflammation, apoptosis, and angiogenesis.
Hypothesis: 1. To determine the effects of hypercoagulability on atherogenesis and atherothrombotic phenotype; 2. To assess the potential of direct oral thrombin inhibition (dabigatran) to attenuate atherothrombosis.
Methods: Mice (TMPRO/PRO:ApoE−/−) with a pro-coagulant phenotype, based on a 90% impaired FIIa mediated protein C activation, were generated and compared to littermate control ApoE−/− mice. Atherosclerosis was studied by two different models: a spontaneous course and a carotid cuff model. In a separate cuff-induced atherosclerosis experiment, we established the effects of direct thrombin inhibition by treating TMPRO/PRO:ApoE−/− mice with dabigatran etexilate-supplemented high-fat diet or placebo for 6 weeks. Furthermore, we investigated arterial thrombus formation in vivo in a FeCl3 carotid injury model.
Results and Conclusions: Plasma fibrinogen, factors II and X, and thrombin-antithrombin levels were markedly increased in TMPRO/PRO:ApoE−/− mice compared to controls. TMPRO/PRO:ApoE−/− animals demonstrated severe atherosclerotic development when compared to ApoE−/− mice in both the spontaneous course model (n=10 per group; P<0.0001), but also in the collar-induced one (n=10 per group; P<0.0007). TMPRO/PRO:ApoE−/− lesions had a marked vulnerable character and were more thrombogenic as assessed with a FeCl3 carotid injury model. In contrast, dabigatran had a strong and protective effect against atherosclerosis in TMPRO/PRO:ApoE−/− mice by inhibiting stenosis from an average of 89% of the total lumen to less than 10% (n=10 per group, p<0.0001). These data confirm that thrombin may be a target for therapeutic intervention against CVD progression.
- © 2010 by American Heart Association, Inc.