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

Abstract

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 100/100 Ldlr ؊/؊ ), 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 100/100 Ldlr ؊/؊ mice than in hCRP 0/0 Apob 100/100 Ldlr ؊/؊ 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 ؉/0 Apob 100/100 Ldlr ؊/؊ 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 ؉/0 Apob 100/100 Ldlr ؊/؊ 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.acute-phase protein ͉ apolipoprotein B100 ͉ coronary artery disease ͉ low-density lipoprotein ͉ plaques

C-reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: Role of mitogen-activated protein kinases

“…This dose was selected after conducting pilot studies to achieve serum hCRP concentrations comparable to the extensively used hCRP transgenic mouse model. 21 Euglycemic Hyperinsulinemic Clamp. Indwelling catheters were inserted into the right jugular vein and the left carotid artery of rats under general anesthesia (ketamine 75 mg/kg, xylazine 10 mg/kg, intraperitoneally) and exteriorized from the back of the neck.…”

C-Reactive Protein-Bound Enzymatically Modified Low-Density Lipoprotein Does Not Transform Macrophages into Foam Cells

“…In vivo, also, CRP is not proatherogenic (48 -52). Recently, in ApoB 100/100 Ldlr Ϫ/Ϫ murine model of human-like atherosclerosis, CRP was found to be atheroprotective and the importance of CRP-LDL interaction in this protection was noted (53). Combined data support the view that CRP is beneficial and lowering its serum level may not be advisable (10,54).…”

Phosphoethanolamine-complexed C-reactive protein: A pharmacological-like macromolecule that binds to native low-density lipoprotein in human serum

“…Recently, in ApoB 100/100 Ldlr −/− murine model of human-like atherosclerosis, CRP was found to be atheroprotective and the importance of CRP-LDL interaction in this protection was noted [ 36 ]. We have not yet started in vivo experiments using injections of CRP-PEt complexes into murine models of atherosclerosis but we hypothesize that the pharmacologic intervention of endogenous CRP by PEt-based compounds, or using the properties of exogenously prepared CRP-PEt complexes to capture native LDL, may turn out to be an effective approach to accelerate CRP-mediated prevention of the development of atherosclerosis.…”