The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice

• Published in: The Journal of pharmacology and experimental therapeutics 2012-11, Vol.343 (2), p.253-257
• Main Authors: Lee, Illkyu-O, Kratz, Mario T, Schirmer, Stephan H, Baumhäkel, Magnus, Böhm, Michael
• Format: Article
• Language: English
• Subjects: Animals; Antithrombins - pharmacology; Apolipoproteins E - genetics; Apolipoproteins E - physiology; Benzimidazoles - pharmacology; beta-Alanine - analogs & derivatives; beta-Alanine - pharmacology; Blood Pressure - drug effects; Body Weight - drug effects; Collagen - metabolism; Dabigatran; Endothelium, Vascular - drug effects; Ethidium - analogs & derivatives; Fluorescent Dyes; Heart Rate - drug effects; Male; Mice; Mice, Knockout; Microscopy, Fluorescence; Oxidative Stress - drug effects; Plaque, Atherosclerotic - genetics; Plaque, Atherosclerotic - prevention & control; Thrombin - antagonists & inhibitors
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.112.194837

The recently developed oral anticoagulant dabigatran (Dabi) etexilate directly inhibits thrombin after activation by plasma esterases to dabigatran. Thrombin is involved in the pathogenesis of atherosclerosis. We investigated the effects of direct thrombin inhibition on atherosclerosis and endothelial function in a hypercholesterolemic mouse model with accelerated atherosclerosis {[apolipoprotein E-deficient (ApoE(-/-)] mice}. ApoE(-/-) mice were treated with a cholesterol-rich diet for 12 weeks and either dabigatran etexilate (900 mg/kg body weight) or vehicle. Wild-type (C57/B6) mice served as control. Endothelial function was assessed with carbachol (endothelium dependent) by using glyceroltrinitrate (endothelium independent) as control in aortic rings. Atherosclerotic lesion formation was evaluated with Oil Red staining, and vascular collagen content was determined by Sirius Red staining. Reactive oxygen species (ROS) production was determined by semiquantitative immunohistochemical staining. Measurement of dabigatran plasma levels (622.3±169 ng/ml) and a performed coagulation test (diluted thrombin time) revealed a relevant anticoagulatory concentration. Dabigatran etexilate attenuated increased atherosclerotic plaque formation [ApoE(-/-) Dabi: 16.1±3.8% of ApoE(-/-) control; p