© 1995 American Heart Association, Inc.
Articles |
Mildly Oxidized LDL Induces Platelet Aggregation Through Activation of Phospholipase A2
From the Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, University of Munich, Germany.
Correspondence to Prof Dr W. Siess, Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Universität München, Pettenkoferstr 9, 80336 München, Germany.
Abstract Native LDL and LDL oxidized under various conditions
were compared in terms of their ability to activate
platelets. Native LDL did not induce platelet shape change or
aggregation, even at high concentrations (2 mg protein/mL). LDL was
mildly oxidized with either CuSO4 (mox-LDL) or
3-(N-morpholino)sydnonimine (SIN-1–LDL).
Analysis of mox-LDL and SIN-1–LDL showed a small
increase of dienes (E234nm from 0.28±0.04 to 0.55±0.09,
mean±SD) and thiobarbituric acid–reactive substance (from 0 to
10.6±1.5 nmol/mg, mean±SEM), no change in apo B electrophoretic
mobility, and a minor (12% to 30%) decrease in polyunsaturated fatty
acid content. Interestingly, this small oxidative modification of LDL
dramatically changed its effect on platelets. Irreversible
aggregation and secretion were induced by a threshold concentration of
0.4 mg protein/mL. In contrast, LDL thoroughly oxidized with
CuSO4 (ox-LDL) did not aggregate platelets. Although
mox-LDL was depleted in antioxidants (
- and
-tocopherol, - and ß-carotene, and other
carotenoids), incubation of mox-LDL with exogenous
-tocopherol did not reverse its ability to induce
platelet aggregation and secretion. Preincubation of platelets
with the cyclooxygenase inhibitor
aspirin or the phospholipase A2 inhibitors
trifluoperazine, quinacrine, 4-bromophenacyl bromide, and
propranolol completely prevented platelet aggregation
and secretion caused by mox-LDL or SIN-1–LDL. These results indicate
that mildly oxidized LDL activates platelets through a
phospholipase A2/cyclooxygenase–dependent pathway.
The complete inhibition of mox-LDL–induced platelet aggregation by
aspirin could contribute to its beneficial effect in
cardiovascular disease.
Key Words: platelet activation • LDL peroxidation • tocopherol • aspirin • SIN-1–LDL • LDL fatty acids
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