001 THROMBIN INHIBITION WITH MELEGOTRAN PREVENTS PLAQUE RUPTURE IN APOLIPOPROTEIN E KNOCKOUT MICE

*S. Karanam¹, R. F. Danielson², C. Jackson¹.¹Bristol Heart Institute, University of Bristol, Bristol, UK; ²AstraZeneca R&D, Mölndal, Sweden

Atherosclerotic plaque rupture and subsequent thrombogenicity cause the majority of acute coronary events. Therefore, the effect of the oral direct thrombin inhibitor Melagatran on atherosclerotic plaques was investigated in the fat-fed apolipoprotein E (apoE) knockout mouse, in which plaque ruptures occur in the brachiocephalic artery after 8 weeks on a high fat diet. Eighty male apoE knockout mice, 6–8 weeks old, were fed a diet containing 21% fat and 0.15% cholesterol for 8 weeks. Forty mice were treated with 500 μmol/Kg body weight/day of Melagatran throughout the 8 weeks. The brachiocephalic artery was removed following perfusion fixation with formalin at a constant pressure of 100 mmHg and embedded in paraffin. Computerised morphometry of serial sections was used to measure the areas of the plaque, the media, and the lumen. The number of buried fibrous layers within the plaque and presence or absence of acute plaque rupture was also recorded. Immunostaining was used to detect the expression of markers of inflammation and thrombogenicity. Melagatran treatment at 500 μmol/Kg bodyweight/day significantly reduced plaque size from 38.5 ± 5.6 to 7.3 ± 1.3 × 10³ μm² (−81%; p < 0.001) and the incidence of plaque rupture from 0.43 ± 0.10 to 0.10 ± 0.05 (−77%; p < 0.05). Immunohistochemical analysis of serial sections showed reduced staining for various inflammatory and thrombogenic markers. This study supports the hypothesis that serial accumulation of thrombus through repeated episodes of non-fatal plaque rupture contributes to atherosclerotic plaque growth in the apoE knockout mouse and also that inhibition of thrombin activity may be a useful strategy for inhibiting plaque rupture.

002 EXPRESSION OF PEROXISOME PROLIFERATORS-ACTIVATOR RECEPTOR-δ AND RETINOID X RECEPTORS IN ENDOTHELIAL CELLS

*L. Piqueras, T. D. Warner, D. Bishop-Bailey.William Harvey …