on September 21, 2006
Published online before print September 21, 2006, doi: 10.1161/01.ATV.0000246797.05781.ad
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Submitted on May 30, 2006
Accepted on September 12, 2006
Melagatran Reduces Advanced Atherosclerotic Lesion Size and May Promote Plaque Stability in Apolipoprotein E- Deficient Mice
Florian Bea ;
From the Medizinische Klinik III (F.B., J.K., M.P., S.S., H.K., E.B.) and Medizinische Klinik I (B.I.), Universität Heidelberg, Heidelberg, Germany; and the Department of Pathobiology and Nutritional Science (M.E.R.), University of Washington, Seattle.
* To whom correspondence should be addressed. E-mail: erwin_blessing{at}med.uni-heidelberg.de.
Objective--Inflammatory mechanisms are involved in atherosclerotic plaque rupture and subsequent thrombin formation. Thrombin not only plays a central role in thrombus formation and platelet activation, but also in the induction of inflammatory processes. We assessed the hypothesis that melagatran, a direct thrombin inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions.
Methods and Results--Melagatran (500 µmol/kg/d) or control diet was administered to apolipoprotein E-deficient mice (n=54) with advanced atherosclerotic lesions. Treatment reduced lesion progression in brachiocephalic arteries (P<0.005). Morphometric analysis confirmed that thrombin inhibition promoted plaque stability and resulted in thicker fibrous caps (28.4±14.2 µm versus 20.8±12.0 µm; P<0.05), increased media thickness (29.3±9.6 µm versus 24.4±6.7 µm; P<0.05), and smaller necrotic cores (73 537±41301 µm2 versus 126 819±51730 µm2; P<0.0005). Electro mobility shift assays revealed reduced binding activity of nuclear factor 
B (P<0.05) and activator protein-1 (P<0.05) in aortas of treated mice. Furthermore, immunohistochemistry demonstrated reduced staining for matrix metalloproteinase (MMP)-9 (P<0.05). Melagatran had no significant effect on early lesion formation in C57BL/6J mice.
Conclusions--The direct thrombin inhibitor melagatran reduces lesion size and may promote plaque stability in apolipoprotein E-deficient mice, possibly through reduced activation of proinflammatory transcription factors and reduced synthesis of MMP-9.
Key words: direct thrombin inhibitor • atherosclerosis • plaque • inflammation • transcription factors • MMP-9
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