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

Abstract

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 ϳ10-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.

Platelet-vessel wall interactions in atherosclerotic disease

“…Furthermore, PF4 mayd irectly promote atherosclerosis by the inhibitionofLDL catabolism, whichismediated in part by competing for binding to the LDLr eceptor,b yp romoting interactions with cell-associatedc hondroitin sulfate proteoglycans and by disrupting the normal endocytic trafficking of LDL/ LDL-Rcomplexes (5). In addition, PF4markedlyenhances the esterification and uptakeofoxidized LDL by macrophages (6). Amongthe wide range of chemokines found to be expressed in atherosclerotic lesions, the deposition of PF4has been correlated with lesion severity and symptomatic atherosclerosis, suggesting thatpersistent plateletactivation maycontribute to the evolution of vascularlesions.Given thatPF4 and oxidized LDLcolocalize in macrophage-derived foam cells of atherosclerotic lesions, this mechanism likelypromotes vascularlipid accumulation (7).…”

Weight Loss–Associated Induction of Peroxisome Proliferator–Activated Receptor-α and Peroxisome Proliferator–Activated Receptor-γ Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice

“…Platelet factor 4 enhances the uptake of ox-LDL by macrophages. 42 Thus, decreased expression of platelet factor 4 can result in decreased uptake of ox-LDL and thus decreased foam cell generation. The amount of ox-LDL in the aortic arch from diet-restricted DKO mice was indeed lower than that in free-fed mice.…”

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

“…Macrophages internalise apoptotic cell fragments, bacterial endotoxins, and oxLDL, leading to lipid accumulation and foam cell formation. Interestingly, PF4 in macrophages correlates with the presence and the extension of atherosclerotic lesions (13,14). CD40 ligand (CD40L, CD154) and its receptor CD40 are costimulatory molecules of the tumour necrosis factor (TNF) and TNF receptor family.…”