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Research ArticleCardiovascular

The Effects of Direct Thrombin Inhibition with Dabigatran on Plaque Formation and Endothelial Function in Apolipoprotein E-Deficient Mice

Illkyu-O. Lee, Mario T. Kratz, Stephan H. Schirmer, Magnus Baumhäkel and Michael Böhm
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 253-257; DOI: https://doi.org/10.1124/jpet.112.194837
Illkyu-O. Lee
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
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Mario T. Kratz
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
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Stephan H. Schirmer
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
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Magnus Baumhäkel
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
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Michael Böhm
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
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Abstract

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.

Footnotes

  • This study was supported by a grant from Boehringer Ingelheim. M.Ba. and M.Bö. have received honoraria from Boehringer Ingelheim. S.H.S. and M.Bö. are supported by the Deutsche Forschungsgemeinschaft [Grant KFO 196] and the Ministry of Science of the State of the Saarland.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.194837.

  • ABBREVIATIONS:

    ApoE
    apolipoprotein E
    ApoE(−/−)
    apolipoprotein E deficient
    Dabi
    dabigatran
    DHE
    dihydroethidium
    dTT
    diluted thrombin time
    NO
    nitric oxide
    ROS
    reactive oxygen species
    WT
    wild type.

  • Received March 28, 2012.
  • Accepted July 24, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleCardiovascular

Dabigatran and Endothelial Function

Illkyu-O. Lee, Mario T. Kratz, Stephan H. Schirmer, Magnus Baumhäkel and Michael Böhm
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 253-257; DOI: https://doi.org/10.1124/jpet.112.194837

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Research ArticleCardiovascular

Dabigatran and Endothelial Function

Illkyu-O. Lee, Mario T. Kratz, Stephan H. Schirmer, Magnus Baumhäkel and Michael Böhm
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 253-257; DOI: https://doi.org/10.1124/jpet.112.194837
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