Published online before print May 26, 2005, doi: 10.1161/01.ATV.0000171983.95612.90
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Role of C-Reactive Protein in Atherogenesis
Can the Apolipoprotein E Knockout Mouse Provide the Answer?
From the Central Laboratory Animal Facility (K.R., E.W.) and the Institutes of Pathology (H.-A.L., D.B., S.C.S.), Clinical Chemistry and Laboratory Medicine (M.T., K.J.L.), Medical Biometry, Epidemiology, and Informatics (M.B.), and Medical Microbiology and Hygiene (M.H., S. Bhakdi), Johannes Gutenberg University Mainz, Germany; and the Department of Biochemistry (S. Black, D.S.), Case Western Reserve University, Cleveland, Ohio.
Correspondence to Sucharit Bhakdi, Institute of Medical Microbiology and Hygiene Johannes Gutenberg University Mainz Obere Zahlbacherstr 67 55131 Mainz, Germany. E-mail sbhakdi{at}uni-mainz.de
Objective— Human C-reactive protein (CRP) was reported to accelerate atherosclerotic lesion development in male but not in female apolipoprotein E (apoE) knockout mice. Here, mice expressing rabbit CRP (rbCRP) were crossbred onto apoE knockout animals, and the effect on atherogenesis was studied.
Methods and Results— Hemolytic complement activity could not be detected in apoE knockout mice. Furthermore, in contrast to human complement, neither rabbit nor human CRP complexed to modified low-density lipoprotein–activated murine complement. At 52 weeks, rbCRP levels were similar in male and female transgenic animals. Serum cholesterol levels were equivalent in female animals irrespective of rbCRP expression, whereas rbCRP–positive males had significantly higher serum cholesterol levels than the rbCRP-negative counterparts. All mice exhibited extensive atherosclerotic lesions, as studied en face, and no differences were noted between rbCRP-negative and rbCRP-positive animals. Atherosclerotic luminal obstruction of aortic arch and first-order neck branches did not differ significantly between rbCRP-positive and rbCRP-negative mice. There was no correlation between rbCRP levels and atherosclerotic lesion formation.
Conclusions— No marked effect of rbCRP on the formation of moderately advanced atherosclerotic lesions could be discerned in the apoE knockout mouse. Because of the oddities of the mouse complement system, however, this may not be a good model to investigate the role of CRP in human atherosclerosis.
Transgenic mice expressing rabbit CRP were crossbred onto apolipoprotein E knockout animals, and the animals were monitored for the development of atherosclerotic lesions. We failed to detect a significant influence of CRP transgenesis on atherogenesis in apoE knockout mice.
Key Words: C-reactive protein • atherosclerosis • complement • transgene murine model
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