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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3056-3063
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Smooth muscle cell surface tissue factor pathway activation by
oxidized low-density lipoprotein requires cellular lipid
peroxidation
Marc S. Penn,
Mei-Zhen Cui,
Allison L. Winokur,
John Bethea,
Thomas A. Hamilton,
Paul E. DiCorleto, and
Guy M. Chisolm
From the Departments of Cardiology, Cell Biology, and
Immunology, Lerner Research Institute, Cleveland Clinic Foundation,
Cleveland, OH.
Tissue factor, which is expressed in vascular lesions, increases
thrombin production, blood coagulation, and smooth muscle cell
proliferation. We demonstrate that oxidized low-density lipoprotein (LDL) induces surface tissue factor pathway activity (ie, activity of
the tissue factor:factor VIIa complex) on human and rat smooth muscle
cells. Tissue factor messenger RNA (mRNA) 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-dependent
mechanism, because antioxidants blocked the enhanced tissue factor
pathway activity by oxidized LDL, but not the increased mRNA or protein
induction. We separated total lipid extracts of oxidized LDL using
high-performance liquid chromatography (HPLC). This yielded 2 major
peaks that induced tissue factor activity. Of the known oxysterols
contained in the first peak, 7 - or 7 -hydroxy or 7-ketocholesterol
had no effect on tissue factor pathway activity; however,
7-hydroperoxycholesterol increased tissue factor pathway activity
without induction of tissue factor mRNA. Tertiary butyl
hydroperoxide also increased tissue factor pathway activity,
suggesting that lipid hydroperoxides, some of which exist in
atherosclerotic lesions, activate the tissue factor pathway. We
speculate that thrombin production could be elevated via a mechanism
involving peroxidation of cellular lipids, contributing to arterial
thrombosis after plaque rupture. Our data suggest a mechanism by which
antioxidants may offer a clinical benefit in acute coronary syndrome
and restenosis.
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