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J. Biol. Chem., Vol. 275, Issue 42, 33176-33183, October 20, 2000
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From the Section of Experimental Atherosclerosis, NHLBI, National
Institutes of Health, Bethesda, Maryland 20892
Evidence suggests that aggregated low density
lipoprotein (AgLDL) accumulates in atherosclerotic lesions. Previously,
we showed that AgLDL induces and enters surface-connected compartments
(SCC) in human monocyte-derived macrophages by a process we have named patocytosis. Most AgLDL taken up by these macrophages in the absence of
serum is stored in SCC and remains undegraded. We now show that
macrophages released AgLDL (prepared by vortexing or treatment with
phospholipase C or sphingomyelinase) from their SCC when exposed to
10% human lipoprotein-deficient serum (LPDS). Macrophages also took up
AgLDL in the presence of LPDS, but subsequently released it. In both
cases, the released AgLDL was disaggregated. Although the AgLDL that
macrophages took up could not pass through a 0.45-µm filter, >60%
of AgLDL could pass this filter after release from the macrophages.
Disaggregation of AgLDL was verified by gel-filtration chromatography
and electron microscopy that also showed particles larger than LDL,
reflecting fusion of LDL that aggregates. The factor in serum that
mediated AgLDL release and disaggregation was plasmin generated
from plasminogen by macrophage urokinase plasminogen activator.
AgLDL release was decreased >90% by inhibitors of plasmin (
Plasmin-mediated Macrophage Reversal of Low Density
Lipoprotein Aggregation*
,, and
-amino
caproic acid and anti-plasminogen mAb), and also by inhibitors of
urokinase plasminogen activator (plasminogen activator inhibitor-1 and
anti-urokinase plasminogen activator mAb). Moreover, plasminogen could
substitute for LPDS and produce similar macrophage release and
disaggregation of AgLDL. Because only plasmin bound to the macrophage
surface is protected from serum plasmin inhibitors, interaction of
AgLDL with macrophages was necessary for reversal of its aggregation by
LPDS. The released disaggregated LDL particles were competent to
stimulate LDL receptor-mediated endocytosis in cultured fibroblasts.
Macrophage-mediated disaggregation of aggregated and fused LDL is a
mechanism for transforming LDL into lipoprotein structures
size-consistent with lipid particles found in atherosclerotic lesions.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Contributed equally to the results of this report.
§
To whom correspondence should be addressed: Section of Experimental
Atherosclerosis, NHLBI, National Institutes of Health, Bldg. 10, Rm.
5N-113, 10 Center Dr., MSC 1422, Bethesda, MD 20892-1422. Tel.:
301-496-4827; Fax: 301-402-4359; E-mail: kruthh@nhlbi.nih.gov.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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