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

Author:

Sachais Bruce S.1,Kuo Alice1,Nassar Taher1,Morgan Jeanelle1,Kariko Katalin1,Williams Kevin Jon1,Feldman Michael1,Aviram Michael1,Shah Neelima1,Jarett Leonard1,Poncz Mortimer1,Cines Douglas B.1,Higazi Abd Al-Roof1

Affiliation:

1. 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.

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 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference65 articles.

1. Evidence for a pivotal role of platelets in vascular reocclusion and restenosis.;LeBreton;Cardiovas Res.,1996

2. Atherosclerotic plaque rupture and thrombosis. Evolving concepts.;Fuster;Circulation.,1990

3. Infiltration and thrombosis in atherogenesis. A study using immunofluorescent techniques.;Woolf;Am J Pathol.,1967

4. Platelet-endothelial interactions in inflamed mesenteric venules.;Frenette;Blood.,1998

5. Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin.;Frenette;Proc Natl Acad Sci U S A.,1995

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3