title: 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.
abstract: 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 catabolism of low-density lipoprotein (LDL) by human vascular cells. The results of the study demonstrated that defensin stimulated the binding of (125)I-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 alpha(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 alpha-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. (Blood. 2000;96:1393-1398)
authors.affiliation: Departments of Clinical Biochemistry, Surgery, and Medicine and the Center for Research, Prevention and Treatment of Atherosclerosis, Hebrew University-Hadassah Medical Centers, Jerusalem, Israel. higazi@mail.med.upenn.edu
authors.forename: A A
authors.initials: AA
authors.lastname: Higazi
authors.forename: T
authors.initials: T
authors.lastname: Nassar
authors.forename: T
authors.initials: T
authors.lastname: Ganz
authors.forename: D J
authors.initials: DJ
authors.lastname: Rader
authors.forename: R
authors.initials: R
authors.lastname: Udassin
authors.forename: K
authors.initials: K
authors.lastname: Bdeir
authors.forename: E
authors.initials: E
authors.lastname: Hiss
authors.forename: B S
authors.initials: BS
authors.lastname: Sachais
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
authors.forename: E
authors.initials: E
authors.lastname: Leitersdorf
authors.forename: D B
authors.initials: DB
authors.lastname: Cines
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D023082:Defensins; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; D023082:Defensins; D008077:Lipoproteins, LDL; D011506:Proteins; D011509:Proteoglycans; D011973:Receptors, LDL