This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/12/2787    most recent 01.ATV.0000246797.05781.adv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bea, F. Articles by Blessing, E. Search for Related Content PubMed PubMed Citation Articles by Bea, F. Articles by Blessing, E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Blood Thinners Related Collections Pericardial disease Animal models of human disease Pathophysiology Genetically altered mice Thrombin Other anticoagulants Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2787.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Melagatran Reduces Advanced Atherosclerotic Lesion Size and May Promote Plaque Stability in Apolipoprotein E– Deficient Mice

Florian Bea; Joerg Kreuzer; Michael Preusch; Sandra Schaab; Berend Isermann; Michael E. Rosenfeld; Hugo Katus; Erwin Blessing

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.

Correspondence to Erwin Blessing, MD, Medizinische Klinik III, Universität Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. 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.

Effects of chronic thrombin inhibition with melagatran was evaluated in advanced lesions of apoE-deficient mice. Melagatran attenuated lesion progression and promoted plaque stability, possibly through inhibiting activation of proinflammatory transcription factors and reduced synthesis of MMP-9.

Key Words: direct thrombin inhibitor • atherosclerosis • plaque • inflammation • transcription factors • MMP-9

This article has been cited by other articles:

				J. I. Borissoff, H. M.H. Spronk, S. Heeneman, and H. ten Cate Is thrombin a key player in the 'coagulation-atherogenesis' maze? Cardiovasc Res, June 1, 2009; 82(3): 392 - 403. [Abstract] [Full Text] [PDF]

				X. Li, T. Syrovets, S. Paskas, Y. Laumonnier, and T. Simmet Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction J. Immunol., July 15, 2008; 181(2): 1215 - 1223. [Abstract] [Full Text] [PDF]

				M. Popovic, Y. Laumonnier, L. Burysek, T. Syrovets, and T. Simmet Thrombin-induced expression of endothelial CX3CL1 potentiates monocyte CCL2 production and transendothelial migration J. Leukoc. Biol., July 1, 2008; 84(1): 215 - 223. [Abstract] [Full Text] [PDF]