Suppressing thrombin generation is compatible with the development of atherosclerosis in mice

Thrombin has been proposed to play a key role in the development of atheros clerosis, both by promoting fibrin deposition into the atherosclerotic vess el wall and also by signalling through thrombin receptors. Unfortunately, m ice homozygous for a deletion of the prothrombin gene (FII) die in utero, m aking a direct assessment of the role of thrombin during atherogenesis diff icult. We have assessed the contribution of thrombin-dependent processes to vascular lipid lesion formation in the atherosclerosis-prone apolipoprotei n E (ApoE)-deficient mice by inhibiting thrombin generation with warfarin. ApoE - / - mice were treated with warfarin at a dose that increased the pro thrombin time (PT) more than 10-fold (250-375 mug/kg body weight/ day) for 12 weeks from the age of 12 weeks onwards. The extent and composition of th e vascular lipid lesions that developed were assessed using oil red O to me asure neutral lipid in the vessel wall and quantitative immuno-fluoresence to measure fibrin(ogen) levels as well as macrophage and smooth muscle cell numbers. Mice treated with warfarin developed lesions both in the aortic s inus and the descending aorta to the same degree as mice receiving no treat ment (28,351 +/- 350 mum(2)/mouse treated with warfarin versus 27,952 +/- 7 50 mum(2)/control mouse; P=.86). However, the amount of fibrin(ogen) deposi ted in the vessel wall was decreased by more than 60% (34 +/- 11 arbitrary units in warfarin treated mice versus 92 +/- 11 arbitrary units in control mice; P<.01). Staining of macrophage and for smooth muscle cell markers was unaltered by treatment with warfarin. We conclude that suppressing thrombi n generation does not alter the development of vascular lipid lesions in mi ce with a severe disorder of lipid metabolism, despite a marked reduction i n fibrin(ogen) deposition. <(c)> 2001 Elsevier Science Ltd. All rights rese rved.