PubMed · 11432384
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R Chilton. 2001. Web alert.. https://doi.org/10.1007/s11883-001-0018-7
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C-reactive protein (CRP), an acute-phase reactant, is present in atherosclerotic human arterial intima in association with lipids. In the present work we studied interactions between CRP and LDL on microtitre wells, where either CRP or LDL was immobilized. LDL was modified by vortex-mixing, oxidation, or by lipolysis with phospholipase A(2) or with sphingomyelinase or a combination of trypsin and cholesterol esterase. We found that CRP bound only to LDL modified by trypsin/cholesterol esterase or by sphingomyelinase and that this binding was Ca(2+)-dependent. In these two forms of modified LDL, non-esterified cholesterol was susceptible to cholesterol oxidase, indicating exposure of non-esterified cholesterol on particle surfaces and suggesting a role for non-esterified cholesterol in mediating CRP binding. Consistent with this hypothesis were the following findings: (i) increasing the amount of non-esterified cholesterol in LDL with cyclodextrin increased, and decreasing its amount decreased, the binding of CRP to LDL; (ii) modification of non-esterified cholesterol in LDL by cholesterol oxidase decreased the binding of CRP to LDL; and (iii) CRP bound to purified non-esterified cholesterol. The binding was Ca(2+)-dependent and could be competed out with phosphocholine. Taken together, these findings suggest that CRP can bind to modified lipoproteins, notably to the non-esterified cholesterol on their surface. These interactions may be related to the suggested role of CRP in the local inflammation present in atherosclerotic plaques.
Foam cells found in atherosclerotic lesions are believed to derive from macrophages that take up aggregated low-density lipoprotein (LDL) particles bound to the extracellular matrix of arterial walls. C-reactive protein (CRP) is an acute-phase protein found in atherosclerotic lesions, which when immobilized on a solid phase, can bind and cluster LDL particles in a calcium-dependent manner. In the present study, we examined whether CRP-bound aggregated LDL could be taken up by macrophages in culture. CRP molecules were aggregated in the presence of calcium and immobilized on the surface of polystyrene microtitre wells. Human LDL added to the wells bound to and aggregated on the immobilized CRP, also in a calcium-dependent manner. On incubation with macrophages, the immobilized CRP-bound LDL aggregates were readily taken up by the cells, as demonstrated by immunofluorescence microscopy, by the cellular accumulation of cholesterol and by the overexpression of adipophilin. Immunofluorescence microscopy and flow-cytometry analysis established that the uptake of the LDL-CRP complex was not mediated by the CRP receptor CD32. These observations with immobilized CRP and LDL, approximating the conditions that exist in the extracellular matrix of the arterial wall, thus suggest that CRP may contribute to the formation of foam cells in atherosclerotic lesions by causing the aggregation of LDL molecules that are then taken up by macrophages through a CD32-independent pathway.
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