© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Modification of Type III VLDL, Their Remnants, and VLDL From ApoE-Knockout Mice by p-Hydroxyphenylacetaldehyde, a Product of Myeloperoxidase Activity, Causes Marked Cholesteryl Ester Accumulation in Macrophages
From the Departments of Biochemistry and Medicine and the Robarts Research Institute (S.C.W., D.B.M., R.A.H., M.W.H.), University of Western Ontario, London, Ontario, Canada; and the Departments of Medicine and of Molecular Biology and Pharmacology (S.L.H. and J.W.H.), Washington University School of Medicine, St Louis, Mo.
Abstract—Very low density
lipoproteins (VLDLs) from apolipoprotein (apo) E2/E2 subjects with type
III hyperlipoproteinemia, VLDL remnants, and
VLDL from apoE-knockout (EKO) mice are taken up poorly by
macrophages. The present study examined whether VLDL
modification by the reactive aldehyde
p-hydroxyphenylacetaldehyde (pHA) enhances cholesteryl
ester (CE) accumulation by J774A.1 macrophages. pHA is the
major product derived from the oxidation of L-tyrosine
by myeloperoxidase and is a component of human atherosclerotic lesions.
Incubation of J774A.1 cells with native type III VLDL, their remnants,
and EKO-VLDL increased cellular CE by only 3-, 5-, and 5-fold,
respectively, compared with controls. In striking contrast, cells
exposed to VLDL modified by purified pHA (pHA-VLDL) exhibited marked
increases in cellular CE of 38-, 47-, and 35-fold, respectively
(P
0.0001). Addition of the lipoprotein lipase
inhibitor tetrahydrolipstatin decreased cellular CE
accumulation induced by the 3 pHA-modified VLDL preparations by 73%,
59%, and 73%, respectively. Addition of the acyl coenzyme
A:cholesterol acyltransferase inhibitor DuP 128
to cells incubated with the pHA-modified lipoproteins decreased
cellular CE by 100%, 82%, and 95%, respectively, but had no effect
on cellular triglycerides. To examine whether the type A
scavenger receptors (SR-As) mediated the uptake of pHA-VLDL,
incubations were performed in the presence of polyinosine (poly I), a
polynucleotide known to block binding to SR-As (types I and
II), or in cells preincubated with interferon-
(IFN-), a
cytokine known to decrease expression of SR-A type I.
Coincubation of pHA-VLDL with poly I reduced cellular CE by only 38%,
44%, and 49%, respectively, whereas coincubation with IFN- reduced
CE by only 18%, 27%, and 65%, respectively. In marked contrast to
pHA-VLDL, both poly I and IFN- inhibited, by>95%, CE accumulation
induced by copper-oxidized VLDL. These results demonstrate a novel
mechanism for the conversion of type III VLDLs, their remnants, and
EKO-VLDL into atherogenic particles and suggest that macrophage
uptake of pHA-VLDL (1) requires catalytically active lipoprotein
lipase, (2) involves acyl coenzyme A:cholesterol
acyltransferase–mediated cholesterol esterification, and
(3) involves pathways distinct from the SR-A.
Key Words: foam cells • atherosclerosis • in vitro • lipoproteins • reactive aldehydes
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