Platelet factor 4 enhances the binding of oxidized low-density lipoprotein to vascular wall cells.
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 approximately 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.
Nassar
Taher
T
Department of Clinical Biochemistry, the Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Sachais
Bruce S
BS
Akkawi
Sa'ed
S
Kowalska
Maria Anna
MA
Bdeir
Khalil
K
Leitersdorf
Eran
E
Hiss
Edna
E
Ziporen
Leah
L
Aviram
Michael
M
Cines
Douglas
D
Poncz
Mortimer
M
Higazi
Abd Al-Roof
AA
D019943:Amino Acid Substitution; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology; D001792:Blood Platelets / Q000502:physiology*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology*; D014644:Genetic Variation; D006801:Humans; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000378:metabolism*; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D010978:Platelet Factor 4 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011485:Protein Binding; D011509:Proteoglycans / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014471:Umbilical Veins
D008077:Lipoproteins, LDL; D011509:Proteoglycans; D011994:Recombinant Proteins; C099252:oxidized low density lipoprotein; D010978:Platelet Factor 4