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(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

Sucharit Bhakdi, MD^*; Michael Torzewski, MD^*; Kerstin Paprotka; Steffen Schmitt, PhD; Hala Barsoom; Prapat Suriyaphol, PhD; Shan-Rui Han, MD; Karl J. Lackner, MD; Matthias Husmann, MD

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

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