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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1393-1398
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The  -defensins stimulate proteoglycan-dependent
catabolism of low-density lipoprotein by vascular cells: a new class of
inflammatory apolipoprotein and a possible contributor to
atherogenesis
Abd Al-Roof Higazi,
Taher Nassar,
Tomas Ganz,
Daniel J. Rader,
Raphael Udassin,
Khalil Bdeir,
Edna Hiss,
Bruce S. Sachais,
Kevin
Jon Williams,
Eran Leitersdorf, and
Douglas B. Cines
From the Departments of Clinical Biochemistry, Surgery,
and Medicine and the Center for Research, Prevention and Treatment of
Atherosclerosis, Hebrew University-Hadassah Medical Centers,
Jerusalem, Israel; Department of Pathology and Laboratory Medicine and
the Department of Medicine, University of Pennsylvania, Philadelphia;
Division of Endocrinology, Diabetes and Metabolic Diseases, Department
of Medicine, Thomas Jefferson University, Philadelphia, PA; and
the Division of Pulmonary and Critical Care, Department of Medicine,
University California at Los Angeles.
Inflammation may contribute to the pathogenesis of atherosclerosis.
On the basis of previous reports that human atherosclerotic lesions
contain  -defensins, a class of cationic proteins released by
activated neutrophils, the study was designed to ask whether defensins
modulate the binding and catabolism of low-density lipoprotein (LDL) by
human vascular cells. The results of the study demonstrated that defensin stimulated the binding of 125I-LDL to
cultured human umbilical vein endothelial cells, smooth muscle cells,
and fibroblasts approximately 5-fold in a dose-dependent and saturable
manner. Defensin and LDL formed stable complexes in solution and on
cell surfaces. Stimulation of LDL binding by defensin was not inhibited
by antibodies against the LDL-receptor (LDL-R), or by recombinant
receptor-associated protein, which blocks binding of ligands to the
2-macroglobulin receptor/LDL-R-related protein and
other LDL-R family members. Furthermore, defensin stimulated the
binding, endocytosis, and degradation of LDL by fibroblasts lacking
LDL-R. Stimulation of LDL degradation by defensin was inhibited
approximately 75% by low concentrations of heparin (0.2 units/mL) and
was similarly reduced in CHO cells lacking heparan-sulfate-containing
proteoglycans. The effect of defensin was substantially increased in
cells overexpressing the core protein of the syndecan-1 heparan sulfate
proteoglycan. The -defensins released from activated neutrophils may
provide a link between inflammation and atherosclerosis by
changing the pattern of LDL catabolism from LDL-R to the less
efficient LDL-R-independent, proteoglycan-dependent pathway.
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