title: The beneficial effects of a direct thrombin inhibitor, dabigatran etexilate, on the development and stability of atherosclerotic lesions in apolipoprotein E-deficient mice : dabigatran etexilate and atherosclerosis.
abstract: OBJECTIVE
  Dabigatran etexilate (DE) constitutes a novel, direct thrombin inhibitor. Regarding the association of thrombin with atherogenesis, we assessed the effects of DE on the development and stability of atherosclerotic lesions in apolipoprotein-E deficient (ApoE-/-) mice.
  
  
  METHODS
  Fifty male ApoE-/- mice were randomized to receive western-type diet either supplemented with DE 7.5 mg DE/g chow) (DE-group, n = 25) or matching placebo as control (CO-group, n = 25) for 12 weeks. After this period, all mice underwent carotid artery injury with ferric chloride and the time to thrombotic total occlusion (TTO) was measured. Then, mice were euthanatized and each aortic arch was analyzed for the mean plaque area, the content of macrophages, elastin, collagen, nuclear factor kappaB (NFκB), vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1).
  
  
  RESULTS
  DE-group showed significantly longer TTO compared to CO-group (8.9 ± 2.3 min vs 3.5 ± 1.1 min, p < 0.001) and the mean plaque area was smaller in DE-group than CO-group (441.00 ± 160.01 × 10(3) μm(2) vs 132.12 ± 32.17 × 10(3) μm(2), p < 0.001). Atherosclerotic lesions derived from DE-treated mice showed increased collagen (p = 0.043) and elastin (p = 0.031) content, thicker fibrous caps (p < 0.001) and reduced number of internal elastic lamina ruptures per mm of arterial girth (p < 0.001) when compared to CO-group. Notably, DE treatment seemed to promote plaque stability possibly by reducing concentrations of NFκB, VCAM-1, macrophages and MMP-9 and increasing TIMP-1 within atherosclerotic lesions (p < 0.05).
  
  
  CONCLUSIONS
  DE attenuates arterial thrombosis, reduces lesion size and may promote plaque stability in ApoE-/- mice. The plaque-stabilizing effects of chronic thrombin inhibition might be the result of the favorable modification of inflammatory mechanisms.
authors.affiliation: Center of Experimental Surgery, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessioustr, 11527, Athens, Greece. nkado@med.uoa.gr
authors.forename: Nikolaos P E
authors.initials: NP
authors.lastname: Kadoglou
authors.forename: Petros
authors.initials: P
authors.lastname: Moustardas
authors.forename: Michael
authors.initials: M
authors.lastname: Katsimpoulas
authors.forename: Alkistis
authors.initials: A
authors.lastname: Kapelouzou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kostomitsopoulos
authors.forename: Katrin
authors.initials: K
authors.lastname: Schafer
authors.forename: Alkiviadis
authors.initials: A
authors.lastname: Kostakis
authors.forename: Christos D
authors.initials: CD
authors.lastname: Liapis
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000069604:Dabigatran; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000991:Antithrombins; D001057:Apolipoproteins E; D001562:Benzimidazoles; D016328:NF-kappa B; D011725:Pyridines; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019010:Vascular Cell Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000069604:Dabigatran