Adding to the controversy: Continuously‐infused human C‐reactive protein reduces atherosclerosis in apolipoprotein E‐deficient mice

Abstract

The role of C‐reactive protein (CRP) in atherosclerosis mouse models remains controversial, with studies showing both proatherogenic and no effects. We hypothesized that the discrepancies might relate to the use of azide‐ or endotoxin‐contaminated native (n) CRP, its episodic administration, to the use of CRP transgenic vs. non‐transgenic mice, or to biased sampling of the aorta in evaluating atherosclerotic lesions. We administered azide‐ and endotoxin‐free human nCRP (n=11) or placebo (n=11) to 12‐week‐old apolipoprotein E‐deficient (apoE−/−) male mice as a continuous infusion for 4 weeks (20.4 μg/day). Animals treated with nCRP developed fewer lesions (7.24 ± 1.59%) in the whole aorta than controls (9.90 ± 2.11%) (p= 0.0026; R2 = 0.3578). When aortic regions were analyzed separately, the extent of atherosclerotic lesions showed significant differences for nCRP‐treated vs. controls in the thoraco‐abdominal region (3.14 ± 1.27% vs. 4.67 ± 1.89%) (p = 0.0322; R2 =0.2004); but the differences were not significant in the aortic arch (3.71 ±1.15% vs. 4.63 ± 1.16%) (p = 0.0715; R2 = 0.1465), the iliac region (0.40 % ± 0.35 vs. 0.62; ± 0.30%) (p = 0.1247; R2 = 0.1086), or the aortic root (65.02 ± 7.81% vs. 64.71± 9.65%) (p= 0.9393; R2 = 0.0004). These comparisons show an unexpected reduction of atherosclerosis in nCRP‐treated mice. They also emphasize the methodological importance of examining the whole aorta, rather than arbitrarily selected regions, to gain a valid understanding of atherosclerosis in this model.