Continuously-Infused Human C-Reactive Protein Is Neither Proatherosclerotic Nor Proinflammatory in Apolipoprotein E–Deficient Mice

Abstract

Studies of human native C-reactive protein (nCRP) in mice have shown effects ranging from proatherogenic, to antiatherogenic, to no effect. It is likely that these disparities are related to (a) the use, in some studies, of contaminated nCRP, or to (b) variation in CRP levels associated with either its episodic administration or the use of CRP-transgenic mice. In our study, 12-week-old male apolipoprotein E-deficient (apoE (-/-)) mice, maintained on a Western diet, received azide- and endotoxin-free nCRP (n = 23) or placebo (n = 23) continuously via osmotic pumps (20.4 microg/day) for 4 weeks. CRP-treated and control mice developed similar atherosclerotic lesions in whole aortas (nCRP: 10.4 +/- 4.7% vs. controls: 11.7 +/- 4.4%, P = 0.76) and aortic roots (nCRP: 65.0 +/- 7.8% vs. controls: 64.7 +/- 9.7%, P = 0.94). No differences were observed in macrophage or T-lymphocyte infiltrates and there was no meaningful change in VCAM-1 or IL-6 expression, in the levels of soluble VCAM-1, or in circulating proinflammatory (IL-1 beta, IL-6, IL-12p40, IL-12p70, TNF-alpha, and INF-gamma), or anti-inflammatory (IL-4 and IL-10) cytokines. We conclude that continuous infusion of uncontaminated nCRP in apoE (-/-) mice is not associated with increased atherosclerosis, does not alter systemic or local inflammation, and does not affect endothelial activation. These observations suggest that alternative approaches to study CRP (perhaps using different pentraxins in the mouse model or using a rabbit model instead of a mouse model) are needed to evaluate the effects of pentraxins on atherosclerosis.