RT Journal Article
SR Electronic
T1 The Effects of Direct Thrombin Inhibition with Dabigatran on Plaque Formation and Endothelial Function in Apolipoprotein E-Deficient Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 253
OP 257
DO 10.1124/jpet.112.194837
VO 343
IS 2
A1 Illkyu-O. Lee
A1 Mario T. Kratz
A1 Stephan H. Schirmer
A1 Magnus Baumhäkel
A1 Michael Böhm
YR 2012
UL http://jpet.aspetjournals.org/content/343/2/253.abstract
AB 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 < 0.001], decreased collagen content [ApoE(−/−) Dabi: 49.1 ± 10% of ApoE(−/−) control; p = 0.01], and ROS production in dihydroethidium staining [ApoE(−/−) Dabi: 46.3 ± 5.4% of ApoE(−/−) control; p = 0.005] in parallel to an improvement of endothelial function [ApoE(−/−) control 42.6 ± 2.7 versus ApoE(−/−) Dabi 62.9 ± 3.3% of phenylephrine-induced contraction; p = 0.001] at 100 μmol carbachol. These data suggest that direct thrombin inhibition in a relevant dosage improved endothelial function and reduced atherosclerotic lesion size, collagen content, and oxidative stress in hypercholesterolemic atherosclerosis. Interference with the coagulation system might provide a therapeutic target to modify atherosclerotic disease progression.