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

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 mu mol/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 mu m versus 20.8 +/- 12.0 mu m; P < 0.05), increased media thickness (29.3 +/- 9.6 mu m versus 24.4 +/- 6.7 mu m; P < 0.05), and smaller necrotic cores (73 537 +/- 41301 mu m(2) versus 126 819 +/- 51730 mu m(2); P < 0.0005). Electro mobility shift assays revealed reduced binding activity of nuclear factor kappa 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.