© 1995 American Heart Association, Inc.
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Tissue Factor Pathway Inhibitor Activity Associated With LDL Is Inactivated by Cell- and Copper-Mediated Oxidation
From the Institut National de la Santé et de la Recherche Médicale, Unité de Recherches sur les Lipoprotéines et l'Athérogénèse, Hôpital de la Pitié, Paris, France.
Correspondence to Philippe Lesnik and M. John Chapman, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherches sur les Lipoprotéines et l'Athérogénèse, U-321, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83, Bd de l'Hôpital, 75651 Paris Cedex 13, France.
Abstract Human plasma contains a multivalent, Kunitz-type
proteinase inhibitor termed tissue factor pathway
inhibitor (TFPI), which is a specific inhibitor
of the action of the factor VII(a)–tissue factor complex in
coagulation. A major fraction of plasma TFPI is transported in
association with LDL. Because LDL may undergo oxidation in the
arterial wall during atherogenesis, we examined the effect
of copper- and cell-mediated oxidative modification on TFPI activity
associated with LDL. Oxidation mediated by copper ions resulted in a
significant inactivation of LDL-associated TFPI (60% to 72% at 24
hours with 2.5 µmol/L CuCl2). The inactivation of TFPI
was strongly negatively correlated with both an increase in the net
electrical charge of LDL (r=-.80, P
.0001) and
with the production of thiobarbituric acid–reactive substances
(r=-.78, P.0001) and lipid peroxides
(r=-.80, P.0001). Cell-mediated oxidation,
involving incubation of LDL for 48 hours with either monocyte-like THP1
cells or human monocytes in Ham's F-10 medium, effected a significant
decrease (64% and 75%, respectively) in LDL-associated TFPI activity.
By contrast, prolonged exposure of LDL to purified soybean
lipoxygenase (5000 U/mL) was less effective in
inactivating TFPI (47% reduction after incubation for 72 hours at
37°C). We subsequently investigated the mechanism(s) that may
underlie such inactivation. Oxidation of LDL is accompanied by the
generation of various aldehydes, including malondialdehyde and
4-hydroxynonenal. Chemical modification with these aldehydes revealed a
significant inverse correlation between the progressive loss of TFPI
activity and both the increase in net electrical charge
(r=-.93, P.0001) and the derivatization of
free amino acid residues of LDL (r=-.90,
P.0001). Specific chemical modification of lysine amino
groups by acetylation similarly led to inactivation of
LDL-associated TFPI activity. TFPI activity was almost totally
abolished (<1.4%) when the TNBS reactivities of acetylated
LDL, malondialdehyde-modified LDL, and 4-hydroxynonenal–modified LDL
were 31%, 21%, and 43% that of native LDL, respectively. Our data
demonstrate that expression of LDL-associated anticoagulant activity is
markedly decreased as a consequence of the oxidative process, and
suggest that the progressive aldehydic derivatization of apo B of LDL,
and of the associated TFPI protein, may contribute to this phenomenon.
Because tissue factor is overexpressed in the
atheromatous plaque, it may exert a marked local
procoagulant effect. The oxidative inactivation of LDL-associated TFPI
will therefore effectively neutralize its inhibitory action
on tissue factor activity, resulting in a disequilibrium in favor of
coagulation.
Key Words: anticoagulant activity • thrombosis • monocytes
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