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

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.