© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
LDL Modified by Hypochlorous Acid Is a Potent Inhibitor of Lecithin-Cholesterol Acyltransferase Activity
From the Linus Pauling Institute (M.R.M., A.C.C., B.F.), Oregon State University, Corvallis, and Lawrence Berkeley National Laboratory (T.M.F.), Life Sciences Division, University of California at Berkeley.
Correspondence to Balz Frei, PhD, Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512. E-mail balz.frei{at}orst.edu
Abstract—Modification
of low density lipoprotein (LDL) by myeloperoxidase-generated HOCl has
been implicated in human atherosclerosis. Incubation of
LDL with HOCl generates several reactive intermediates, primarily
N-chloramines, which may react
with other biomolecules. In this study, we investigated the effects of
HOCl-modified LDL on the activity of lecithin-cholesterol
acyltransferase (LCAT), an enzyme essential for high density
lipoprotein maturation and the antiatherogenic reverse
cholesterol transport pathway. We exposed human LDL (0.5 mg
protein/mL) to physiological concentrations of HOCl
(25 to 200 µmol/L) and characterized the resulting LDL modifications
to apolipoprotein B and lipids; the modified LDL was subsequently
incubated with apolipoprotein B–depleted plasma (density >1.063 g/mL
fraction), which contains functional LCAT. Increasing concentrations of
HOCl caused various modifications to LDL, primarily, loss of lysine
residues and increases in
N-chloramines and
electrophoretic mobility, whereas lipid hydroperoxides were only minor
products. LCAT activity was extremely sensitive to HOCl-modified
LDL and was reduced by 23% and 93% by LDL preincubated with 25 and
100 µmol/L HOCl, respectively. Addition of 200 µmol/L ascorbate or
N-acetyl derivatives of
cysteine or methionine completely prevented LCAT inactivation by LDL
preincubated with 
200 µmol/L HOCl. Protecting the free thiol groups
of LCAT with 5,5'-dithio-bis-(2-nitrobenzoic acid) before exposure to
HOCl-modified LDL, which inhibits lipid hydroperoxide–mediated
inactivation of LCAT, failed to prevent the loss of enzyme activity.
Our data indicate that
N-chloramines from
HOCl-modified LDL mediate the loss of plasma LCAT activity and provide
a novel mechanism by which myeloperoxidase-generated HOCl may promote
atherogenesis.
Key Words: chloramines • HDL • LDL • lecithin-cholesterol acyltransferase • hypochlorous acid
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