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Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 May 2002, Vol. 99, No. 10, pp. 3613-3622 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic itinerary, resulting in retention of low-density lipoprotein on the cell surface Bruce S. Sachais, Alice Kuo, Taher Nassar, Jeanelle Morgan, Katalin Kariko, Kevin Jon Williams, Michael Feldman, Michael Aviram, Neelima Shah, Leonard Jarett, Mortimer Poncz, Douglas B. Cines, and Abd Al-Roof Higazi From the Departments of Pathology and Laboratory Medicine, Neurosurgery, and Pediatrics, University of Pennsylvania, Philadelphia; the Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA; Lipid Research Laboratory, Rambam Medical Center and Rappaport Institute for Research in the Medical Sciences, Haifa, Israel, and the Department of Clinical Biochemistry, Hadassah Medical Organization, Jerusalem, Israel. 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 µg/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. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Zernecke, E. Shagdarsuren, and C. Weber Chemokines in Atherosclerosis: An Update Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1897 - 1908. [Abstract] [Full Text] [PDF] C. A. Gleissner, P. von Hundelshausen, and K. Ley Platelet Chemokines in Vascular Disease Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1920 - 1927. [Abstract] [Full Text] [PDF] E. Cavusoglu, E. Kornecki, M. B. Sobocka, A. Babinska, Y. H. Ehrlich, V. Chopra, S. Yanamadala, C. Ruwende, M. O. Salifu, L. T. Clark, et al. Association of Plasma Levels of F11 Receptor/Junctional Adhesion Molecule-A (F11R/JAM-A) With Human Atherosclerosis J. Am. Coll. 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