Native C-Reactive Protein Increases Whereas Modified C-Reactive Protein Reduces Atherosclerosis in Apolipoprotein E–Knockout Mice

Abstract

Background-C-reactive protein (CRP) may have proatherogenic but also vasoprotective properties. We tested the hypothesis that the configuration of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) determines these different characteristics in an in vivo model. Methods and Results-We investigated the effects of human nCRP and mCRP on the development of atherosclerosis in apolipoprotein E-knockout (ApoE Ϫ/Ϫ ) mice. Treatment with nCRP for 8 weeks (2.5 mg/kg SC weekly) resulted in a 4-fold-higher mean aortic plaque area in 14-week-old female ApoE Ϫ/Ϫ mice compared with the saline controls. In contrast, mean plaque size was decreased by Ϸ50% in mCRP-treated ApoE Ϫ/Ϫ mice (2.5 mg/kg SC weekly). Using immunohistochemistry, we report the natural presence of the mCRP antigen in saline controls. mCRP antigen was expressed in smooth muscle cells and extracellularly in the vicinity of the plaques to a similar level in both CRP-treated groups and saline controls. mCRP and ApoB colocalized with macrophages and were equally upregulated in all aortic plaques. Vascular cell adhesion molecule expression was increased, and CD154 and intercellular adhesion molecule showed a trend for higher expression in nCRP-treated compared with mCRP-treated mice. CD154 expression in the vessel wall and plaque size correlated significantly. mCRP-treated ApoE Ϫ/Ϫ exhibited higher serum levels of the antiinflammatory interleukin-10 compared with the other 2 groups. Conclusions-Here, we show that mCRP and nCRP have opposite effects on atherosclerosis in ApoE Ϫ/Ϫ mice. These data may explain in part the conflicting activities previously reported for CRP in models of atherogenesis.

Monomeric CRP contributes to complement control in fluid phase and on cellular surfaces and increases phagocytosis by recruiting factor H

“…32 In ApoE knockout mice, pCRP increases and mCRP reduces the plaque development. 33 In addition, in atherosclerotic lesions, mCRP colocalizes with complement proteins C3b, iC3b and the terminal complement complex, as well as with oxidized and modified LDL. 27,34,35 This colocalization suggests a cooperative effect of mCRP and Figure 5 Factor H-mCRP complexes bind phosphocholine.…”

Topological Localization of Monomeric C-reactive Protein Determines Proinflammatory Endothelial Cell Responses

“…Moreover, tissue-associated mCRP, irrespective of its redox state (15), may exert antiatherosclerotic actions, in particular at initial stages of plaque development, by promoting opsonic activation of the early complement pathway and non-inflammatory clearance of damaged cells (14,28,32,33) and by inhibiting foam cell formation (34,35). Overall, these would underlie the seemingly counterintuitive findings of the in vivo atheroprotective effects of Cys-mutated mCRP (18).…”

“…However, subcutaneous administration of Cys-mutated mCRP into ApoE Ϫ/Ϫ mice was found to reduce plaque formation (18). ECs are highly polarized cells with compositionally and functionally distinct plasma membrane domains, i.e.…”

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

“…Recently, in the ApoE knockout mouse, specific differences have been observed between native and modified CRP: with the modified CRP producing smaller plaques than native CRP [132]. These differences were related to the expression of adhesion molecules and the authors of this study have proposed that some varied reports of CRP in atherogenic studies might be due to the differential effects of native and modified CRP [132].…”