LDL increases inactive tissue factor on vascular smooth muscle cell surfaces - Hydrogen peroxide activates latent cell surface tissue factor

Background-Tissue factor,which is required for the initiation of the extrin sic coagulation cascade, is known to be upregulated in cells within atheros clerotic lesions, including smooth muscle cells. Tissue factor expression o n the smooth muscle cell surface could be of pathological significance as a contributor to plaque growth, thrombus formation, and the acute coronary s yndrome after plaque rupture. Methods and Results - In this study, we show that LDL increased tissue fact or mRNA and cell surface protein in smooth muscle cells without a marked in crease in surface tissue factor activity. Hydrogen peroxide activated tissu e factor on the cell surface but did not increase tissue factor mRNA or cel l surface protein. Sequentially added LDL and hydrogen peroxide increased m RNA, cell surface protein, and activity; surface activity was greater than that observed with hydrogen peroxide alone. The action of hydrogen peroxide did not involve a regulatory mechanism associated with the cytoplasmic tai l of tissue factor because a truncated tissue factor lacking the cytoplasmi c tail was activated by hydrogen peroxide. Conclusions-These results suggest a novel 2-step pathway for increased tiss ue factor activity on smooth muscle cell surfaces in which lipoproteins reg ulate synthesis of a latent tissue factor and oxidants activate the protein complex.