Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia

Increased baseline values of the acute-phase reactant C-reactive protein (CRP) are significantly associated with future cardiovascular disease, and some in vitro studies have claimed that human CRP (hCRP) has proatherogenic effects. In vivo studies in apolipoprotein E-deficient mouse models, however, have given conflicting results. We bred atherosclerosis-prone mice (Apob ^100/100Ldlr^-/-), which have human-like hypercholesterolemia, with hCRP transgenic mice (hCRP^+/0) and studied lesion development at 15, 30, 40, and 50 weeks of age. Atherosclerotic lesions were smaller in hCRP^+/0 Apob^100/100Ldlr^-/- mice than in hCRP^0/0Apob^100/100Ldlr^-/- controls, as judged from the lesion surface areas of pinned-out aortas from mice at 40 and 50 weeks of age. In lesions from 40-week-old mice, mRNA expression levels of several genes in the proteasome degradation pathway were higher in hCRP ^+/0Apob^100/100Ldlr^-/- mice than in littermate controls, as shown by global gene expression profiles. These results were confirmed by real-time PCR, which also indicated that the activities of those genes were the same at 30 and 40 weeks in hCRP^+/0Apob ^100/100Ldlr^-/- mice but were significantly lower at 40 weeks than at 30 weeks in controls. Our results show that hCRP is not proatherogenic but instead slows atherogenesis, possibly through proteasome-mediated protein degradation.