The alpha-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis
Aa. Higazi et al., The alpha-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis, BLOOD, 96(4), 2000, pp. 1393-1398
Inflammation may contribute to the pathogenesis of atherosclerosis. On the
basis of previous reports that human atherosclerotic lesions contain alpha-
defensins, a class of cationic proteins released by activated neutrophils,
the study was designed to ask whether defensins modulate the binding and ca
tabolism of low-density lipoprotein (LDL) by human vascular cells. The resu
lts of the study demonstrated that defensin stimulated the binding of I-125
-LDL to cultured human umbilical vein endothelial cells, smooth muscle cell
s, and fibroblasts approximately 5-fold in a dose dependent and saturable m
anner. Defensin and LDL formed stable complexes in solution and on cell sur
faces. Stimulation of LDL binding by defensin was not inhibited by antibodi
es against the LDL-receptor (LDLR), or by recombinant receptor-associated p
rotein, which blocks binding of ligands to the alpha(2)-macroglobulin recep
tor/ LDL-R-related protein and other LDL-R family members. Furthermore, def
ensin stimulated the binding, endocytosis, and degradation of LDL by fibrob
lasts lacking LDL-R, Stimulation of LDL degradation by defensin was inhibit
ed approximately 75% by low concentrations of heparin (0.2 units/mL) and wa
s similarly reduced in CHO cells lacking heparan-sulfate-containing proteog
lycans. The effect of defensin was substantially increased in cells overexp
ressing the core protein of the syndecan-1 heparan sulfate proteoglycan. Th
e alpha-defensins released from activated neutrophils may provide a link be
tween inflammation and atherosclerosis by changing the pattern of LDL catab
olism from LDL-R to the less efficient LDL-R-indebendent, proteoglycan-depe
ndent pathway. (Blood, 2000;96:1393-1398) (C) 2000 by The American Society
of Hematology.