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Journal of Lipid Research, Vol 36, 1971-1986, Copyright © 1995 by Lipid Research, Inc.
A Sevanian, HN Hodis, J Hwang, LL McLeod and H Peterson
The present study describes the toxicity of oxidized LDL towards rabbit
aortic endothelial cells in terms of its lipid components with specific
attention to the cholesterol oxidation products (ChOx) found in oxidized
LDL isolated from human plasma. Measurements of the major ChOx associated
with freshly isolated unmodified LDL, those found in oxidized LDL isolated
from human plasma and LDL subjected to oxidation in vitro are described. We
have confirmed previous findings that most of the cytotoxicity of freshly
isolated human LDL may be attributable to a minor fraction that appears to
be oxidatively modified by several criteria. Moreover, this plasma-derived
oxidized LDL (referred to as LDL) is highly enriched in ChOx, whereas the
content of lipid peroxides or derived products (measured as conjugated
dienes and thiobarbituric acid reacting products) are much lower,
particularly when compared to copper-induced LDL oxidation. Much of the
ChOx found in plasma are associated with LDL, however, the levels and
proportions of the various ChOx found in LDL differ from those produced
after extensive copper- induced oxidation but resemble those produced after
moderate oxidation with copper. The species and concentrations of ChOx
found in LDL when applied as a mixture exhibit considerably more toxicity
than any individual ChOx alone. At non-toxic levels this ChOx mixture
causes an increased influx of several ions, including calcium, an effect
not seen with individual ChOx at comparable doses. Perturbations in ionic
homeostasis, and particularly the sustained increase in intracellular
calcium concentrations, are associated with much of the cytotoxicity, an
effect attributable to the membrane disruptive action of ChOx leading to
altered ion transporter activity. The effect of the ChOx mixture (but not
any individual ChOx) on sodium and potassium flux appears to be due to
enhanced Na+/K(+)-ATPase activity based on the complete inhibition produced
by ouabain under all treatment conditions. These findings also show that
the levels of cholesterol oxidation products found in normal LDL are not
cytotoxic whereas those present in oxidized LDL exceed the toxic threshold
for endothelial cells and account for most of the cytotoxicity produced by
this modified lipoprotein.
ARTICLES
Characterization of endothelial cell injury by cholesterol oxidation products found in oxidized LDL
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033, USA.
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