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Thromb Haemost 2008; 99(01): 196-201
DOI: 10.1160/TH07-10-0595
DOI: 10.1160/TH07-10-0595
Animal Models
No effect of C-reactive protein on early atherosclerosis in LDLR-/- / human C-reactive protein transgenic mice
Financial support: This work was supported by the Deutsche Forschungsgemeinschaft (Bh 2/2–3) and by grant 8312–38 62 61/527 from the “Stiftung Rheinland-Pfalz für Innovation”. *MT and KR contributed equally to this work.
Further Information
Correspondence to:
Kurt Reifenberg, DVM
Central Laboratory Animal Facility
Johannes Gutenberg University
Obere Zahlbacherstrasse 67
55131 Mainz, Germany
Phone: +49 6131 39 33325
Fax: +49 6131 39 30220
Email: reifenbe@uni-mainz.de
Publication History
Received:
05 October 2007
Accepted after major revision:
01 November 2007
Publication Date:
24 November 2017 (online)
summary
The association between increased concentrations of C-reactive protein (CRP) and future cardiovascular events is well established. However, it is currently unclear whether this clinical observation represents an epiphenomenon or whether the pentraxin may actively promote the development of atherosclerosis. Experimental studies with knockout mice with a defect in apolipoprotein E (ApoE-/-) have been used to investigate the role of CRP in atherogenesis, but the results obtained have been contradictory so far. Since knockout mice with a defect in low density lipoprotein receptor (LDLR-/-) may represent a better model of atherogenesis compared to ApoE-/- animals, we undertook experiments to investigate the atherogenic potential of CRP using LDLR-/- knockout mice. We crossbred CRP transgenic animals expressing the human CRP pentraxin (huCRP) to LDLR-/- mice, fed the resulting double mutants a pro-atherogenic Western type diet (WTD) for four, eight or 12 weeks, respectively, and quantitated atherosclerotic lesion development. Significant differences of lesion size or lesion composition could not be detected between the huCRP-positive LDLR-/- mice and the huCRP–negative LDLR-/- controls corroborating the contention that CRP does not play a pathogenetic role in early murine atherogenesis.
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References
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- 6 Reifenberg K, Lehr HA, Baskal D. et al. Role of C-reactive protein in atherogenesis: can the apolipoprotein E knockout mouse provide the answer?. Arterioscler Thromb Vasc Biol 2005; 25: 1641-1646.
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- 22 Lin CS, Xia D, Yun JS. et al. Expression of rabbit C-reactive protein in transgenic mice. Immunol Cell Biol 1995; 73: 521-531.
- 23 Torzewski J. C-reactive protein and atherogenesis: new insights from established animal models. Am J Pathol 2005; 167: 923-925.
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- 25 Buono C, Come CE, Witztum JL. et al. Influence of C3 deficiency on atherosclerosis. Circulation 2002; 105: 3025-3031.
- 26 Bhatia VK, Yun S, Leung V. et al. Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol 2007; 170: 416-426.
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Correspondence to:
Kurt Reifenberg, DVM
Central Laboratory Animal Facility
Johannes Gutenberg University
Obere Zahlbacherstrasse 67
55131 Mainz, Germany
Phone: +49 6131 39 33325
Fax: +49 6131 39 30220
Email: reifenbe@uni-mainz.de
-
References
- 1 Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007; 49: 2129-2138.
- 2 Scirica BM, Morrow DA. Is C-reactive protein an innocent bystander or proatherogenic culprit? The verdict is still out. Circulation 2006; 113: 2128-2134.
- 3 Verma S, Devaraj S, Jialal I. Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation 2006; 113: 2135-2150.
- 4 Paul A, Ko KW, Li L. et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficientmice. Circulation 2004; 109: 647-655.
- 5 Trion A, de Maat MP, Jukema JW. et al. No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-leiden/human C-reactive protein transgenic mice. Arterioscler Thromb Vasc Biol 2005; 25: 1635-1640.
- 6 Reifenberg K, Lehr HA, Baskal D. et al. Role of C-reactive protein in atherogenesis: can the apolipoprotein E knockout mouse provide the answer?. Arterioscler Thromb Vasc Biol 2005; 25: 1641-1646.
- 7 Hirschfield GM, Gallimore JR, Kahan MC. et al. Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 2005; 102: 8309-8314.
- 8 Tennent GA, Hutchinson WL, Kahan MC. et al. Transgenic human CRP is not pro-atherogenic, pro-atherothrombotic or pro-inflammatory in apoE(-/-) mice. Atherosclerosis 2007; 21: 21.
- 9 Ciliberto G, Arcone R, Wagner EF. et al. Inducible and tissue-specific expression of human C-reactive protein in transgenic mice. Embo J 1987; 6: 4017-4022.
- 10 Price CP, Trull AK, Berry D. et al. Development and validation of a particle-enhanced turbidimetric immunoassay for C-reactive protein. J Immunol Methods 1987; 99: 205-211.
- 11 Eda S, Kaufmann J, Roos W. et al. Development of a new microparticle-enhanced turbidimetric assay for C-reactive protein with superior features in analytical sensitivity and dynamic range. J Clin Lab Anal 1998; 12: 137-144.
- 12 Paigen B, Morrow A, Holmes PA. et al. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 1987; 68: 231-240.
- 13 Lehr HA, Sagban TA, Ihling C. et al. Immunopa-thogenesis of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet. Circulation 2001; 104: 914-920.
- 14 Lehr HA, Mankoff DA, Corwin D. et al. Application of photoshop-based image analysis to quantification of hormone receptor expression in breast cancer. J Histochem Cytochem 1997; 45: 1559-1565.
- 15 Lehr HA, van der Loos CM, Teeling P. et al. Complete chromogen separation and analysis in double immunohistochemical stains using Photoshop-based image analysis. J Histochem Cytochem 1999; 47: 119-126.
- 16 Ishibashi S, Brown MS, Goldstein JL. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest 1993; 92: 883-893.
- 17 Bhakdi S, Torzewski M, Klouche M. et al. Complement and atherogenesis: binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arterioscler Thromb Vasc Biol 1999; 19: 2348-2354.
- 18 Bhakdi S, Torzewski M, Paprotka K. et al. Possible protective role for C-reactive protein in atherogenesis: complement activation by modified lipoproteins halts before detrimental terminal sequence. Circulation 2004; 109: 1870-1876.
- 19 Zhang SH, Reddick RL, Piedrahita JA. et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992; 258: 468-471.
- 20 Piedrahita JA, Zhang SH, Hagaman JR. et al. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci USA 1992; 89: 4471-4475.
- 21 Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805-12.
- 22 Lin CS, Xia D, Yun JS. et al. Expression of rabbit C-reactive protein in transgenic mice. Immunol Cell Biol 1995; 73: 521-531.
- 23 Torzewski J. C-reactive protein and atherogenesis: new insights from established animal models. Am J Pathol 2005; 167: 923-925.
- 24 Müller-Eberhard HJ. Molecular organization and function of the complement system. Annu Rev Biochem 1988; 57: 321-347.
- 25 Buono C, Come CE, Witztum JL. et al. Influence of C3 deficiency on atherosclerosis. Circulation 2002; 105: 3025-3031.
- 26 Bhatia VK, Yun S, Leung V. et al. Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol 2007; 170: 416-426.
- 27 Kovacs A, Tornvall P, Nilsson R. et al. Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia. Proc Natl Acad Sci USA 2007; 104: 13768-13773.