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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 2007-2019
Defensin Promotes the Binding of Lipoprotein(a) to Vascular Matrix
Khalil Bdeir,
William Cane,
Gabriela Canziani,
Irwin Chaiken,
John Weisel,
Marlys L. Koschinsky,
Richard M. Lawn,
Peter G. Bannerman,
Bruce S. Sachais,
Alice Kuo,
Mark A. Hancock,
John Tomaszewski,
P.N. Raghunath,
Tomas Ganz,
Abd Al-Roof Higazi, and
Douglas B. Cines
From the Departments of Pathology and Laboratory Medicine, Medicine,
Cell Biology, and Pediatrics, University of Pennsylvania, Philadelphia,
PA; the School of Life and Health Sciences, University of Delaware,
Newark, DE; the Department of Biochemistry, Queen's University,
Kingston, Ontario, Canada; the Division of Cardiovascular Medicine,
Stanford University, Stanford, CA; the Division of Pulmonary and
Critical Care, Department of Medicine, University of California at Los
Angeles, Los Angeles, CA; and the Department of Clinical Biochemistry,
Hebrew University-Hadassah Medical Centers, Jerusalem, Israel.
Retention of lipoproteins within the vasculature is a central event
in the pathogenesis of atherosclerosis. However, the signals that
mediate this process are only partially understood. Prompted by
putative links between inflammation and atherosclerosis, we previously
reported that  -defensins released by neutrophils are present in
human atherosclerotic lesions and promote the binding of lipoprotein(a)
[Lp(a)] to vascular cells without a concomitant increase in
degradation. We have now tested the hypothesis that this accumulation
results from the propensity of defensin to form stable complexes with
Lp(a) that divert the lipoprotein from its normal cellular degradative
pathways to the extracellular matrix (ECM). In accord with this
hypothesis, defensin stimulated the binding of Lp(a) to vascular
matrices approximately 40-fold and binding of the reactants to the
matrix was essentially irreversible. Defensin formed stable,
multivalent complexes with Lp(a) and with its components, apoprotein
(a) and low-density lipoprotein (LDL), as assessed by
optical biosensor analysis, gel filtration, and immunoelectron
microscopy. Binding of defensin/Lp(a) complexes to matrix was inhibited
(>90%) by heparin and by antibodies to fibronectin (>70%), but
not by antibodies to vitronectin or thrombospondin. Defensin increased
the binding of Lp(a) (10 nmol/L) to purified fibronectin more than
30-fold. Whereas defensin and Lp(a) readily traversed the endothelial
cell membranes individually, defensin/Lp(a) complexes lodged on the
cell surface. These studies demonstrate that -defensins released
from activated or senescent neutrophils stimulate the binding of an
atherogenic lipoprotein to the ECM of endothelial cells, a process that
may contribute to lipoprotein accumulation in atherosclerotic lesions.
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