Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation

Tissue factor, which is expressed in vascular lesions, increases thrombin p roduction, blood coagulation, and smooth muscle cell proliferation. We demo nstrate that oxidized low-density lipoprotein (LDL) induces surface tissue factor pathway activity (ie, activity of the tissue factor: factor VIIa com plex) on human and rat smooth muscle cells. Tissue factor messenger RNA (mR NA) was induced by oxidized LDL or native LDL; however, native LDL did not markedly increase tissue factor activity. We hypothesized that oxidized LDL mediated the activation of the tissue factor pathway via an oxidant-depend ent mechanism, because antioxidants blocked the enhanced tissue factor path way activity by oxidized LDL, but not the increased mRNA or protein inducti on, We separated total lipid extracts of oxidized LDL using high-performanc e liquid chromatography (HPLC), This yielded 2 major peaks that induced tis sue factor activity, Of the known oxysterols contained in the first peak, 7 alpha- or 7 beta -hydroxy or 7-ketocholesterol had no effect on tissue fac tor pathway activity; however, 7 beta -hydroperoxycholesterol increased tis sue factor pathway activity without induction of tissue factor mRNA, Tertia ry butyl hydroperoxide also increased tissue factor pathway activity sugges ting that lipid hydroperoxides, some of which exist in atherosclerotic lesi ons, activate the tissue factor pathway. We speculate that thrombin product ion could be elevated via a mechanism involving peroxidation of cellular li pids, contributing to arterial thrombosis after plaque rupture. Our data su ggest a mechanism by which antioxidants may offer a clinical benefit in acu te coronary syndrome and restenosis, (C) 2000 by The American Society of He matology.