Melagatran reduces advanced atherosclerotic lesion size and may promote plaque stability in Apolipoprotein E–deficient mice

F Bea, J Kreuzer, M Preusch, S Schaab… - … , and vascular biology, 2006 - Am Heart Assoc
F Bea, J Kreuzer, M Preusch, S Schaab, B Isermann, ME Rosenfeld, H Katus, E Blessing
Arteriosclerosis, thrombosis, and vascular biology, 2006Am Heart Assoc
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) …
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 κB (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.
Am Heart Assoc
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