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J Biol Chem, Vol. 274, Issue 45, 32112-32121, November 5, 1999
From the Departments of A critical event in atherogenesis is the
interaction of arterial wall macrophages with subendothelial
lipoproteins. Although most studies have investigated this interaction
by incubating cultured macrophages with monomeric lipoproteins
dissolved in media, arterial wall macrophages encounter lipoproteins
that are mostly bound to subendothelial extracellular matrix, and these lipoproteins are often aggregated or fused. Herein, we utilize a
specialized cell-culture system to study the initial interaction of
macrophages with aggregated low density lipoprotein (LDL) bound to
extracellular matrix. The aggregated LDL remains extracellular for a
relatively prolonged period of time and becomes lodged in invaginations
in the surface of the macrophages. As expected, the degradation of the
protein moiety of the LDL was very slow. Remarkably, however,
hydrolysis of the cholesteryl ester (CE) moiety of the LDL was
3-7-fold higher than that of the protein moiety, in stark contrast to
the situation with receptor-mediated endocytosis of acetyl-LDL. Similar
results were obtained using another experimental system in which the
degradation of aggregated LDL protein was delayed by LDL methylation
rather than by retention on matrix. Additional experiments indicated
the following properties of this interaction: (a) LDL-CE
hydrolysis is catalyzed by lysosomal acid lipase; (b)
neither scavenger receptors nor the LDL receptor appear necessary for
the excess LDL-CE hydrolysis; and (c) LDL-CE hydrolysis in
this system is resistant to cellular potassium depletion, which further
distinguishes this process from receptor-mediated endocytosis. In
summary, experimental systems specifically designed to mimic the
in vivo interaction of arterial wall macrophages with
subendothelial lipoproteins have demonstrated an initial period of
prolonged cell-surface contact in which CE hydrolysis exceeds protein degradation.
Unique Cellular Events Occurring during the Initial Interaction
of Macrophages with Matrix-retained or Methylated Aggregated Low
Density Lipoprotein (LDL)
PROLONGED CELL-SURFACE CONTACT DURING WHICH LDL-CHOLESTERYL
ESTER HYDROLYSIS EXCEEDS LDL PROTEIN DEGRADATION
,,,
Medicine and Anatomy
and Cell Biology, Columbia University, New York, New York 10032, the
§ Department of Biochemistry, Weill Medical College of
Cornell University, New York, New York 10021, and the ¶ Division
of Human Genetics, Children's Hospital Research Foundation,
Cincinnati, Ohio 45229
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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