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.