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 atherosclerosis, both by promoting fibrin deposition into the atherosclerotic vessel wall and also by signalling through thrombin receptors. Unfortunately, mice homozygous for a deletion of the prothrombin gene (FII) die in utero, making a direct assessment of the role of thrombin during atherogenesis difficult. We have assessed the contribution of thrombin-dependent processes to vascular lipid lesion formation in the atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice by inhibiting thrombin generation with warfarin. ApoE-/- mice were treated with warfarin at a dose that increased the prothrombin time (PT) more than 10-fold (250-375 microg/kg body weight/day) for 12 weeks from the age of 12 weeks onwards. The extent and composition of the vascular lipid lesions that developed were assessed using oil red O to measure neutral lipid in the vessel wall and quantitative immunofluoresence to measure fibrin(ogen) levels as well as macrophage and smooth muscle cell numbers. Mice treated with warfarin developed lesions both in the aortic sinus and the descending aorta to the same degree as mice receiving no treatment (28,351+/-350 microm2/mouse treated with warfarin versus 27,952+/-750 micro2/control mouse; P = .86). However, the amount of fibrin(ogen) deposited 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 thrombin generation does not alter the development of vascular lipid lesions in mice with a severe disorder of lipid metabolism, despite a marked reduction in fibrin(ogen) deposition.
Grainger
D J
DJ
Department of Medicine, Addenbrooke's Hospital, Box 157, Hills Road, CB2 2QQ, Cambridge, UK. djg15@mole.bio.cam.ac.uk
McWilliam
N A
NA
Baglin
T P
TP
Byrne
C D
CD
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D003864:Depression, Chemical; D004195:Disease Models, Animal; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011517:Prothrombin Time; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology
D000925:Anticoagulants; D001057:Apolipoproteins E; D014859:Warfarin; D005337:Fibrin; D013917:Thrombin