Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation.
Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.
Weis
J R
JR
Department of Medicine, University of Utah Medical Center, Salt Lake City.
Pitas
R E
RE
Wilson
B D
BD
Rodgers
G M
GM
D000925:Anticoagulants / Q000494:pharmacology; D001161:Arteriosclerosis / Q000209:etiology; D001205:Ascorbic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D016264:Dextran Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005167:Factor VII / Q000502:physiology; D005170:Factor X / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011134:Polysaccharides / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D011486:Protein C / Q000096:biosynthesis*; D013925:Thromboplastin / Q000096:biosynthesis*
D000925:Anticoagulants; D008077:Lipoproteins, LDL; D011134:Polysaccharides; D011486:Protein C; D005167:Factor VII; D005170:Factor X; D013925:Thromboplastin; D016264:Dextran Sulfate; C007789:fucoidan; D011341:Probucol; D001205:Ascorbic Acid