Platelet Factor 4 Enhances the Binding of Oxidized Low-density Lipoprotein to Vascular Wall Cells

• Published in: The Journal of biological chemistry 2003-02, Vol.278 (8), p.6187-6193
• Main Authors: Nassar, Taher, Sachais, Bruce S, Akkawi, Sa'ed, Kowalska, Maria Anna, Bdeir, Khalil, Leitersdorf, Eran, Hiss, Edna, Ziporen, Leah, Aviram, Michael, Cines, Douglas, Poncz, Mortimer, Higazi, Abd Al-Roof
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Arteriosclerosis - pathology; Blood Platelets - physiology; Cells, Cultured; CHO Cells; Cricetinae; Endothelium, Vascular - pathology; Endothelium, Vascular - physiology; Genetic Variation; Humans; Immunohistochemistry; Lipoproteins, LDL - metabolism; Microscopy, Confocal; Mutagenesis, Site-Directed; Platelet Factor 4 - chemistry; Platelet Factor 4 - genetics; Platelet Factor 4 - pharmacology; Protein Binding; Proteoglycans - pharmacology; Recombinant Proteins - metabolism; Transfection; Umbilical Veins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M208894200

Accumulation of low-density lipoprotein (LDL)-derived cholesterol by macrophages in vessel walls is a pathogenomic feature of atherosclerotic lesions. Platelets contribute to lipid uptake by macrophages through mechanisms that are only partially understood. We have previously shown that platelet factor 4 (PF4) inhibits the binding and degradation of LDL through its receptor, a process that could promote the formation of oxidized LDL (ox-LDL). We have now characterized the effect of PF4 on the binding of ox-LDL to vascular cells and macrophages and on the accumulation of cholesterol esters. PF4 bound to ox-LDL directly and also increased ox-LDL binding to vascular cells and macrophages. PF4 did not stimulate ox-LDL binding to cells that do not synthesize glycosaminoglycans or after enzymatic cleavage of cell surface heparan and chondroitin sulfates. The effect of PF4 on binding ox-LDL was dependent on specific lysine residues in its C terminus. Addition of PF4 also caused an ∼10-fold increase in the amount of ox-LDL esterified by macrophages. Furthermore, PF4 and ox-LDL co-localize in atherosclerotic lesion, especially in macrophage-derived foam cells. These observations offer a potential mechanism by which platelet activation at sites of vascular injury may promote the accumulation of deleterious lipoproteins and offer a new focus for pharmacological intervention in the development of atherosclerosis.