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C-Reactive Protein-Bound Enzymatically Modified Low-Density Lipoprotein Does Not Transform Macrophages into Foam Cells¹

Sanjay K. Singh^*, Madathilparambil V. Suresh^*, Deborah C. Prayther, Jonathan P. Moorman, Antonio E. Rusiñol and Alok Agrawal^2,*

^* Department of Pharmacology, Department of Internal Medicine, and Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614

The formation of low-density lipoprotein (LDL) cholesterol-loaded macrophage foam cells contributes to the development of atherosclerosis. C-reactive protein (CRP) binds to atherogenic forms of LDL, but the role of CRP in foam cell formation is unclear. In this study, we first explored the binding site on CRP for enzymatically modified LDL (E-LDL), a model of atherogenic LDL to which CRP binds. As reported previously, phosphocholine (PCh) inhibited CRP-E-LDL interaction, indicating the involvement of the PCh-binding site of CRP in binding to E-LDL. However, the amino acids Phe66 and Glu81 in CRP that participate in CRP-PCh interaction were not required for CRP-E-LDL interaction. Surprisingly, blocking of the PCh-binding site with phosphoethanolamine (PEt) dramatically increased the binding of CRP to E-LDL. The PEt-mediated enhancement in the binding of CRP to E-LDL was selective for E-LDL because PEt inhibited the binding of CRP to another PCh-binding site-ligand pneumococcal C-polysaccharide. Next, we investigated foam cell formation by CRP-bound E-LDL. We found that, unlike free E-LDL, CRP-bound E-LDL was inactive because it did not transform macrophages into foam cells. The function of CRP in eliminating the activity of E-LDL to form foam cells was not impaired by the presence of PEt. Combined data lead us to two conclusions. First, PEt is a useful compound because it potentiates the binding of CRP to E-LDL and, therefore, increases the efficiency of CRP to prevent transformation of macrophages into E-LDL-loaded foam cells. Second, the function of CRP to prevent formation of foam cells may influence the process of atherogenesis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01HL071233.

² Address correspondence and reprint requests to Dr. Alok Agrawal, Department of Pharmacology, P.O. Box 70577, East Tennessee State University, Johnson City, TN 37614. E-mail address: agrawal{at}etsu.edu

³ Abbreviations used in this paper: LDL, low-density lipoprotein; CRP, C-reactive protein; E-LDL, enzymatically modified LDL; Apo, apolipoprotein; PCh, phosphocholine; PEt, phosphoethanolamine; PnC, pneumococcal C-polysaccharide; TBS-Ca, TBS containing 0.1% gelatin, 0.02% Tween-20 and 2 mM CaCl₂.

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