Published online before print March 22, 2004, doi: 10.1161/01.CIR.0000124228.08972.26
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:1870-1876.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Possible Protective Role for C-Reactive Protein in Atherogenesis
Complement Activation by Modified Lipoproteins Halts Before Detrimental Terminal Sequence
From the Institute of Medical Microbiology and Hygiene (S.B., K.P., H.B., P.S., S.H., M.H.), Institute for Clinical Chemistry and Laboratory Medicine (M.T., K.J.L.), and Center for Natural Sciences and Medicine (S.S.), Johannes Gutenberg University Mainz, Mainz, Germany.
Correspondence to Sucharit Bhakdi, Institute of Medical Microbiology and Hygiene, Hochhaus am Augustusplatz, D-55101 Mainz, Germany. E-mail sbhakdi{at}mail.uni-mainz.de
Received June 26, 2003; de novo received October 13, 2003; revision received December 31, 2003; accepted January 6, 2004.
Background— Previous work indicated that enzymatically remodeled LDL (E-LDL) might activate complement in atherosclerotic lesions via a C-reactive protein (CRP)–dependent and CRP-independent pathway. We sought to substantiate this contention and determine whether both pathways drive the sequence to completion.
Methods and Results— E-LDL was prepared by sequential treatment of LDL with a protease and cholesteryl esterase. Trypsin, proteinase K, cathepsin H, or plasmin was used with similar results. Functional tests were used to assess total complement hemolytic activity, and immunoassays were used to demonstrate C3 cleavage and to quantify C3a, C4a, C5a, and C5b-9. E-LDL preparations activated complement to completion, independent of CRP, when present above a threshold concentration (100 to 200 µg/mL in 5% serum). Below the threshold, all E-LDL preparations activated complement in dependence of CRP, but the pathway then halted before the terminal sequence. Native LDL and oxidized LDL did not activate complement under any circumstances tested. Immunohistological analyses corroborated the concept that CRP-dependent complement activation inefficiently generates C5b-9.
Conclusions— Binding of CRP to E-LDL is the first trigger for complement activation in the atherosclerotic lesion, but the terminal sequence is thereby spared. This putatively protective function of CRP is overrun at higher E-LDL concentrations, so that potentially harmful C5b-9 complexes are generated.
Key Words: atherosclerosis • lipoproteins • C-reactive protein • immune system • complement
This article has been cited by other articles:
 |
|
 |
|
  V. W.Y. Leung, S. Yun, M. Botto, J. C. Mason, T. H. Malik, W. Song, D. Paixao-Cavalcante, M. C. Pickering, J. J. Boyle, and D. O. Haskard Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Am. J. Pathol., October 1, 2009; 175(4): 1757 - 1767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yun, V. W.Y. Leung, M. Botto, J. J. Boyle, and D. O. Haskard Brief Report: Accelerated Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Lacking the Membrane-Bound Complement Regulator CD59 Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1714 - 1716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Singh, M. V. Suresh, D. C. Prayther, J. P. Moorman, A. E. Rusinol, and A. Agrawal C-Reactive Protein-Bound Enzymatically Modified Low-Density Lipoprotein Does Not Transform Macrophages into Foam Cells J. Immunol., March 15, 2008; 180(6): 4316 - 4322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Patel, C. A. King, S. R. Bailey, J. W. Holt, K. Venkatachalam, A. Agrawal, A. J. Valente, and B. Chandrasekar Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-{kappa}B and C/EBPbeta Activation J. Biol. Chem., September 14, 2007; 282(37): 27229 - 27238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kovacs, P. Tornvall, R. Nilsson, J. Tegner, A. Hamsten, and J. Bjorkegren Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia PNAS, August 21, 2007; 104(34): 13768 - 13773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-R. Ji, Y. Wu, L. Zhu, L. A. Potempa, F.-L. Sheng, W. Lu, and J. Zhao Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRPm FASEB J, January 1, 2007; 21(1): 284 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou, Y. P. Jang, S. R. Kim, and J. R. Sparrow Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium PNAS, October 31, 2006; 103(44): 16182 - 16187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Marsik, R. Sunder-Plassmann, B. Jilma, F. M. Kovar, C. Mannhalter, O. Wagner, H. Rumpold, and G. Endler The C-Reactive Protein +1444C/T Alteration Modulates the Inflammation and Coagulation Response in Human Endotoxemia Clin. Chem., October 1, 2006; 52(10): 1952 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Binder, G. Liebisch, T. Langmann, and G. Schmitz Metabolic Profiling of Glycerophospholipid Synthesis in Fibroblasts Loaded with Free Cholesterol and Modified Low Density Lipoproteins J. Biol. Chem., August 4, 2006; 281(31): 21869 - 21877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Montero, J. Orbe, N. Varo, O. Beloqui, J. I. Monreal, J. A. Rodriguez, J. Diez, P. Libby, and J. A. Paramo C-Reactive Protein Induces Matrix Metalloproteinase-1 and -10 in Human Endothelial Cells: Implications for Clinical and Subclinical Atherosclerosis J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1369 - 1378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-R. Ji, Y. Wu, L. A. Potempa, Y.-H. Liang, and J. Zhao Effect of Modified C-Reactive Protein on Complement Activation: A Possible Complement Regulatory Role of Modified or Monomeric C-Reactive Protein in Atherosclerotic Lesions Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 935 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Pepys, P. N. Hawkins, M. C. Kahan, G. A. Tennent, J. R. Gallimore, D. Graham, C. A. Sabin, A. Zychlinsky, and J. de Diego Proinflammatory Effects of Bacterial Recombinant Human C-Reactive Protein Are Caused by Contamination With Bacterial Products, Not by C-Reactive Protein Itself Circ. Res., November 25, 2005; 97(11): e97 - e103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. S. Speidl, M. Exner, J. Amighi, S. P. Kastl, G. Zorn, G. Maurer, O. Wagner, K. Huber, E. Minar, J. Wojta, et al. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis Eur. Heart J., November 1, 2005; 26(21): 2294 - 2299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Reifenberg, H.-A. Lehr, D. Baskal, E. Wiese, S. C. Schaefer, S. Black, D. Samols, M. Torzewski, K. J. Lackner, M. Husmann, et al. Role of C-Reactive Protein in Atherogenesis: Can the Apolipoprotein E Knockout Mouse Provide the Answer? Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1641 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Trion, M.P.M. de Maat, J.W. Jukema, A. van der Laarse, M.C. Maas, E.H. Offerman, L.M. Havekes, A.J. Szalai, H.M.G. Princen, and J.J. Emeis 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, August 1, 2005; 25(8): 1635 - 1640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. Hirschfield, J. R. Gallimore, M. C. Kahan, W. L. Hutchinson, C. A. Sabin, G. M. Benson, A. P. Dhillon, G. A. Tennent, and M. B. Pepys Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice PNAS, June 7, 2005; 102(23): 8309 - 8314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Pepys CRP or not CRP? That Is the Question Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1091 - 1094. [Full Text] [PDF]
|
|
|
|
|
|
K. E. Taylor, J. C. Giddings, and C. W. van den Berg C-Reactive Protein-Induced In Vitro Endothelial Cell Activation Is an Artefact Caused by Azide and Lipopolysaccharide Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1225 - 1230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ivashchenko, F. Kramer, S. Schafer, A. Bucher, K. Veit, V. Hombach, A. Busch, O. Ritzeler, J. Dedio, and J. Torzewski Protein Kinase C Pathway Is Involved in Transcriptional Regulation of C-Reactive Protein Synthesis in Human Hepatocytes Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 186 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Suresh, S. K. Singh, and A. Agrawal Interaction of Calcium-bound C-reactive Protein with Fibronectin Is Controlled by pH: IN VIVO IMPLICATIONS J. Biol. Chem., December 10, 2004; 279(50): 52552 - 52557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Torzewski, P. Suriyaphol, K. Paprotka, L. Spath, V. Ochsenhirt, A. Schmitt, S.-R. Han, M. Husmann, V. B. Gerl, S. Bhakdi, et al. Enzymatic Modification of Low-Density Lipoprotein in the Arterial Wall: A New Role for Plasmin and Matrix Metalloproteinases in Atherogenesis Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2130 - 2136. [Abstract] [Full Text] [PDF]
|
|