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Journal of Lipid Research, Vol. 49, 1015-1023, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Human C-reactive protein promotes oxidized low density lipoprotein uptake and matrix metalloproteinase-9 release in Wistar rats^*

U. Singh^1,*, M. R. Dasu^1,*, P. G. Yancey, A. Afify^*, S. Devaraj^* and I. Jialal^2,*

^* Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA
Department of Medicine, Vanderbilt University, Nashville, TN

^* This work was supported by National Institutes of Health Grant RO1 HL-074360 to I. J.

Published, JLR Papers in Press, February 2, 2008.

¹ U. Singh and M. R. Dasu contributed equally to this work.

² To whom correspondence should be addressed. e-mail: ishwarlal.jialal{at}ucdmc.ucdavis.edu

C-reactive protein (CRP) is present in the atherosclerotic plaques and appears to promote atherogenesis. Intraplaque CRP colocalizes with oxidized low density lipoprotein (OxLDL) and macrophages in human atherosclerotic lesions. Matrix metalloproteinase-9 (MMP-9) has been implicated in plaque rupture. CRP promotes OxLDL uptake and MMP induction in vitro; however, these have not been investigated in vivo. We examined the effect of CRP on OxLDL uptake and MMP-9 production in vivo in Wistar rats. CRP significantly increased OxLDL uptake in the peritoneal and sterile pouch macrophages compared with human serum albumin (huSA). CRP also significantly increased intracellular cholesteryl ester accumulation compared with huSA. The increased uptake of OxLDL by CRP was inhibited by pretreatment with antibodies to CD32, CD64, CD36, and fucoidin, suggesting uptake by both scavenger receptors and Fc- receptors. Furthermore, CRP treatment increased MMP-9 activity in macrophages compared with huSA, which was abrogated by inhibitors to p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), and nuclear factor (NF)-B but not Jun N-terminal kinase (JNK) before human CRP treatment. Because OxLDL uptake by macrophages contributes to foam cell formation and MMP release contributes to plaque instability, this study provides novel in vivo evidence for the role of CRP in atherosclerosis.

Supplementary key words mechanistic insights • macrophages • sterile pouch

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