Submitted on November 20, 2007
Revised on February 1, 2008
Accepted on February 1, 2008
Human C-reactive protein promotes oxidized low-density lipoprotein uptake and matrix metalloproteinase-9 release in wistar rats
Uma Singh, Mohan R. Dasu, Patricia G. Yancey, Alaa Afify, Sridevi Devaraj, and Ishwarlal Jialal
UCDavis Med Ctr, Sacramento, CA 95817
Corresponding Author: 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 (ox-LDL) and macrophages in human atherosclerotic lesions. MMP-9 has been implicated in plaque rupture. CRP promotes ox-LDL uptake and MMP induction in vitro, however, these have not been investigated in vivo. We examined the effect of CRP on ox-LDL uptake and MMP-9 production in vivo in Wistar rats. CRP significantly increased ox-LDL uptake in the peritoneal and sterile pouch macrophages compared to human serum albumin (huSA). CRP also significantly increased intracellular cholesterol ester accumulation compared to huSA. The increased uptake of ox-LDL by CRP was inhibited by pretreatment with antibodies to CD32, CD64, CD36 and fucoidin, suggesting uptake by both scavenger receptors and Fc gamma receptors. Furthermore, CRP treatment increased MMP-9 activity in macrophages compared to huSA, which was abrogated by inhibitors to p38MAP kinase, ERK and NFKb, but not JNK prior to hCRP treatment. Since ox-LDL uptake by macrophages contribute to foam cell formation and MMP release to plaque instability, this study provides novel in-vivo evidence for the role of CRP in atherosclerosis.
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