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Originally published In Press as doi:10.1074/jbc.M908714199 on August 14, 2000

J. Biol. Chem., Vol. 275, Issue 42, 33176-33183, October 20, 2000
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Plasmin-mediated Macrophage Reversal of Low Density Lipoprotein Aggregation*

Wei-Yang ZhangDagger , Itsuko IshiiDagger , and Howard S. Kruth§

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 (epsilon -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.

Dagger 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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