Defensin promotes the binding of lipoprotein(a) to vascular matrix.
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 alpha-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 alpha-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.
Bdeir
K
K
Departments of Pathology and Laboratory Medicine, Medicine, Cell Biology, and Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
Cane
W
W
Canziani
G
G
Chaiken
I
I
Weisel
J
J
Koschinsky
M L
ML
Lawn
R M
RM
Bannerman
P G
PG
Sachais
B S
BS
Kuo
A
A
Hancock
M A
MA
Tomaszewski
J
J
Raghunath
P N
PN
Ganz
T
T
Higazi
A A
AA
Cines
D B
DB
D001053:Apolipoproteins / Q000097:blood; D053241:Apoprotein(a); D015374:Biosensing Techniques; D001798:Blood Proteins / Q000502:physiology / Q000648:ultrastructure; D002478:Cells, Cultured; D023082:Defensins; D004730:Endothelium, Vascular / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D007700:Kinetics; D017270:Lipoprotein(a) / Q000097:blood* / Q000648:ultrastructure; D008077:Lipoproteins, LDL / Q000097:blood; D016253:Microscopy, Immunoelectron; D011485:Protein Binding; D011506:Proteins / Q000502:physiology* / Q000648:ultrastructure; D014471:Umbilical Veins
D001053:Apolipoproteins; D001798:Blood Proteins; D023082:Defensins; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D011506:Proteins; D053241:Apoprotein(a)