Formation of factor Va by atherosclerotic rabbit aorta mediates factor Xa-catalyzed prothrombin activation.
Vascular cell procoagulant activity may be important in the pathogenesis of atherosclerosis. In previous studies, we described the ability of the atherogenic metabolite homocysteine to activate endothelial cell Factor V, a key coagulation cofactor for thrombin generation. The present study was designed to investigate Factor V activity and Factor Xa-catalyzed prothrombin activation by control and atherosclerotic aorta from normal and hypercholesterolemic rabbits. Factor Xa generated ninefold more thrombin on atherosclerotic aortic segments than on control segments. Atherosclerotic segments activated 125I-prothrombin with Factor Xa in the presence of the thrombin inhibitor dansyl arginine-4-ethylpiperidine amide and cleaved 125I-Factor V. This suggests that increases in vessel-wall Factor V activity and Factor Xa-catalyzed prothrombin activation result from activation of vessel-wall Factor V. 125I-Factor Va peptides generated by atherosclerotic aorta were very similar in molecular weight to those generated by homocysteine-treated cells. When vascular endothelium was mechanically removed by brushing, atherosclerotic vessels still generated four- to fivefold more thrombin than control vessels. These data and results from immunocytochemical studies suggest that Factor V in atherosclerotic vessels is associated with both endothelium and other cells of the lesion. In contrast, Factor V in control vessels is associated primarily with endothelium. The increases in Factor V activity and thrombin formation in the blood vessel wall of hypercholesterolemic rabbits may contribute to the development of atherosclerosis and its complications.
Rodgers
G M
GM
Gladstone Foundation Laboratories for Cardiovascular Disease, University of California, San Francisco 94143.
Kane
W H
WH
Pitas
R E
RE
D000818:Animals; D001011:Aorta / Q000032:analysis / Q000378:metabolism* / Q000473:pathology; D001161:Arteriosclerosis / Q000097:blood* / Q000378:metabolism; D003429:Cross Reactions; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000032:analysis / Q000378:metabolism / Q000473:pathology; D005165:Factor V / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D015943:Factor Va; D015951:Factor Xa; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism; D007118:Immunoassay; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D008297:Male; D011516:Prothrombin / Q000378:metabolism*; D011817:Rabbits; D012697:Serine Endopeptidases / Q000378:metabolism*; D013917:Thrombin / Q000096:biosynthesis
D007074:Immunoglobulin G; D015943:Factor Va; D005165:Factor V; D011516:Prothrombin; D012697:Serine Endopeptidases; D013917:Thrombin; D015951:Factor Xa