title: Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic machinery, resulting in retention of low-density lipoprotein on the cell surface.
abstract: The influence of platelets on the cellular metabolism of atherogenic lipoproteins has not been characterized in detail. Therefore, we investigated the effect of platelet factor 4 (PF4), a cationic protein released in high concentration by activated platelets, on the uptake and degradation of low-density lipoprotein (LDL) via the LDL receptor (LDL-R). LDL-R-dependent binding, internalization, and degradation of LDL by cultured cells were inhibited 50%, 80%, and 80%, respectively, on addition of PF4. PF4 bound specifically to the ligand-binding domain of recombinant soluble LDL-R (half-maximal binding 0.5 microg/mL PF4) and partially (approximately 50%) inhibited the binding of LDL. Inhibition of internalization and degradation by PF4 required the presence of cell-associated proteoglycans, primarily those rich in chondroitin sulfate. PF4 variants with impaired heparin binding lacked the capacity to inhibit LDL. PF4, soluble LDL-R, and LDL formed ternary complexes with cell-surface proteoglycans. PF4 induced the retention of LDL/LDL-R complexes on the surface of human fibroblasts in multimolecular clusters unassociated with coated pits, as assessed by immuno-electron microscopy. These studies demonstrate that PF4 inhibits the catabolism of LDL in vitro in part by competing for binding to LDL-R, by promoting interactions with cell-associated chondroitin sulfate proteoglycans, and by disrupting the normal endocytic trafficking of LDL/LDL-R complexes. Retention of LDL on cell surfaces may facilitate proatherogenic modifications and support an expanded role for platelets in the pathogenesis of atherosclerosis.
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA. Sachais@mail.med.upenn.edu
authors: Bruce S
authors: BS
authors: Sachais
authors: Alice
authors: A
authors: Kuo
authors: Taher
authors: T
authors: Nassar
authors: Jeanelle
authors: J
authors: Morgan
authors: Katalin
authors: K
authors: Kariko
authors: Kevin Jon
authors: KJ
authors: Williams
authors: Michael
authors: M
authors: Feldman
authors: Michael
authors: M
authors: Aviram
authors: Neelima
authors: N
authors: Shah
authors: Leonard
authors: L
authors: Jarett
authors: Mortimer
authors: M
authors: Poncz
authors: Douglas B
authors: DB
authors: Cines
authors: Abd Al-Roof
authors: AA
authors: Higazi
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000648:ultrastructure; D010978:Platelet Factor 4 / Q000378:metabolism* / Q000494:pharmacology*; D011509:Proteoglycans / Q000502:physiology; D011973:Receptors, LDL / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D008077:Lipoproteins, LDL; D011509:Proteoglycans; D011973:Receptors, LDL; D010978:Platelet Factor 4