title: Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice.
abstract: The association between circulating concentrations of C-reactive protein (CRP) and future atherothrombotic events has provoked speculation about a possible pathogenetic role of CRP. However, we show here that transgenic expression of human CRP had no effect on development, progression, or severity of spontaneous atherosclerosis, or on morbidity or mortality, in male apolipoprotein E (apoE)-deficient C57BL/6 mice up to 56 weeks, despite deposition of human CRP and mouse complement component 3 in the plaques. Although female apoE knockouts develop atherosclerosis more rapidly than males, the human CRP transgene is under sex hormone control and is expressed at human levels only in males. We therefore studied only male mice. The concentration of mouse serum amyloid P component, an extremely sensitive systemic marker of inflammation, remained normal throughout except for transient spikes in response to fighting in a few animals, indicating that atherogenesis in this model is not associated with an acute-phase response. However, among human CRP transgenic mice, the circulating CRP concentration was higher in apoE knockouts than in wild-type controls. The higher CRP values were associated with substantially lower estradiol concentrations in the apoE-deficient animals. Human CRP transgene expression is thus up-regulated in apoE-deficient mice, apparently reflecting altered estrogen levels, despite the absence of other systemic signs of inflammation. Extrapolation to human pathology from this xenogeneic combination of human CRP with apoE deficiency-mediated mouse atherosclerosis must be guarded. Nevertheless, the present results do not suggest that human CRP is either proatherogenic or atheroprotective in vivo.
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, London NW3 2PF, United Kingdom.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Gallimore
authors.forename: Melvyn C
authors.initials: MC
authors.lastname: Kahan
authors.forename: Winston L
authors.initials: WL
authors.lastname: Hutchinson
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sabin
authors.forename: G Martin
authors.initials: GM
authors.lastname: Benson
authors.forename: Amar P
authors.initials: AP
authors.lastname: Dhillon
authors.forename: Glenys A
authors.initials: GA
authors.lastname: Tennent
authors.forename: Mark B
authors.initials: MB
authors.lastname: Pepys
mesh_terms: D000210:Acute-Phase Reaction; D000375:Aging / Q000097:blood; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism*; D003176:Complement C3 / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013739:Testosterone / Q000097:blood; D019076:Transgenes / Q000235:genetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D001057:Apolipoproteins E; D003176:Complement C3; D019010:Vascular Cell Adhesion Molecule-1; C036763:monocyte-macrophage differentiation antigen; D013739:Testosterone; D004958:Estradiol; D002097:C-Reactive Protein