Melagatran reduces advanced atherosclerotic lesion size and may promote plaque stability in apolipoprotein E-deficient mice.

Abstract

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 micromol/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 microm versus 20.8+/-12.0 microm; P<0.05), increased media thickness (29.3+/-9.6 microm versus 24.4+/-6.7 microm; P<0.05), and smaller necrotic cores (73,537+/-41,301 microm2 versus 126,819+/-51,730 microm2; P<0.0005). Electro mobility shift assays revealed reduced binding activity of nuclear factor kappaB (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.

• Authors: Florian Bea, Joerg Kreuzer, Michael Preusch, Sandra Schaab, Berend Isermann, Michael E Rosenfeld, Hugo Katus, Erwin Blessing
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 26 Issue 12 Pg. 2787-92 (Dec 2006) ISSN: 1524-4636 [Electronic] United States
• PMID: 16990551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticoagulants
• Apolipoproteins E
• Azetidines
• Benzylamines
• Lipids
• NF-kappa B
• Transcription Factor AP-1
• melagatran
• Thrombin
• Matrix Metalloproteinase 9

Topics

• Animals
• Anticoagulants (pharmacology)
• Apolipoproteins E (genetics, metabolism)
• Atherosclerosis (etiology, metabolism, pathology, prevention & control)
• Azetidines (pharmacology)
• Benzylamines (pharmacology)
• Carotid Stenosis (metabolism, pathology)
• Disease Progression
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation (drug effects)
• Hyperlipidemias (complications, metabolism, pathology)
• Lipids (blood)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (genetics, metabolism)
• Thrombin (antagonists & inhibitors)
• Transcription Factor AP-1 (genetics, metabolism)