This document discusses the role of the complement system in the pathogenesis of atherosclerosis. It summarizes several studies that have found activation of the complement system and deposition of complement components in atherosclerotic plaques. C3 deficiency in mice is shown to result in larger lipid-positive areas and higher macrophage accumulation in plaques. The conclusion is that plaque maturation beyond early foam cell formation depends on an intact complement system, and complement activation should be considered in evaluating other inflammatory parameters associated with atherosclerosis. Complement inhibitors may have potential for preventing or stabilizing vulnerable plaques.

1. Editorial Slides
VP Watch –June 26, 2002 - Volume 2, Issue 25
Complement Inhibitor
A Potential Therapy for Prevention or Stabilization of
Vulnerable Plaque ?

2.  Many components of innate and adaptive
immune system are active in atherosclerotic
plaques (as a chronic inflammatory process).
 The complement system is one of the most
important humoral systems mediating many
reactions that contribute to host defense and
initiating and amplifying inflammation, even in
the pre-immune phase where specific antibodies and
lymphocytes are not available.

3.  Pang et al. in 1979 found that the complement
system may be implicated in the pathogenesis of
cholesterol-induced atherosclerosis in rabbits. 2
 Endothelial cell damage causes complement
activation and endothelial cells overlying
atherosclerotic plaques contain C3 and C5b-9
antigens.

4.  In 1987 Niculescu and colleagues showed
deposition of terminal C5b-9 neo-antigens of
complement system (indicator of complement
activation) in atherosclerosis. 3
 Niculescu et al. also found high levels of C5b-9
in the intimal thickening, fibrotic plaques and the
corresponding media when compared with
normal areas and fatty streaks intima. 6

5.  Seifert et al. found a specific cholesterol-
containing lipid particle in human atherosclerotic
plaques that activates the alternative pathway of
complement in a dose-dependent manner. 4
 The protective effect of C6 deficiency on diet-
induced atherosclerosis suggest that the
terminal complement complex plays an
important and critical role in the progression of
atherosclerotic plaque. 7

6. • Colocalization of CRP with activated
complement components in the
atherosclerotic lesion suggests that CRP
may be a major complement activating
molecule in atherogenesis. 8

7.  As reported in VP Watch of this week,
Buono and colleagues compared extent and
phenotype of diet-induced atherosclerotic
plaque in LDLR-deficient mice with or without
C3 deficiency. 9
 This study shows that serum lipoprotein
profiles and immunoglobulin levels were not
significantly different between the 2
experimental groups (LDLR-KO mice with or
without C3 deficiency). 9

8.  They showed that a greater lipid-positive area in
aortic arch sections in C3-deficient mice than in
controls. 9
 They also found higher macrophage
accumulation, less SMC content, and less
collagen content in aortic sections of C3-
deficient versus control mice.9

9. Conclusion
• Plaque maturation beyond the foam cell stage is
dependent on an intact complement system.
• Complement activation should be considered
when evaluating the mechanisms and prognostic
significance of other inflammatory parameters
associated with atherosclerosis, including CRP
and humoral immune responses.

10. Questions:
• Why fatty streak lesions are increased in C3
deficient mice? Why C3 deficient plaques have
more macrophage density?
• Knowing the role of both cell-mediated and
humoral immune response in atherosclerosis,
the question is which one is more important in
plaque formation (largely present in normal
people) and which one is more important in
plaque complication (only happens in victims of
athero-thrombotic events)?

11. Questions:
• Can complement inhibitor be a potential therapy
for prevention / treatment of vulnerable plaque?
• Since a humanized, recombinant, single-chain
antibody specific for human C5 is clinically
available, it would be interesting to know the
effect of complement inhibition on post-
transplant vasculopathy (coronary
atherosclerosis). 10

12. 1) Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
2) Pang AS, Katz A, Minta JO. C3 deposition in cholesterol-induced atherosclerosis in rabbits: a possible etiologic role
for complement in atherogenesis. J Immunol. 1979 Sep;123(3):1117-22.
3) Niculescu F, Rus HG, Vlaicu R.; Activation of the human terminal complement pathway in atherosclerosis. Clin
Immunol Immunopathol. 1987 Nov;45(2):147-55.
4) Seifert PS, Hugo F, Tranum-Jensen J, Zahringer U, Muhly M, Bhakdi S. Isolation and characterization of a
complement-activating lipid extracted from human atherosclerotic lesions. J Exp Med. 1990 Aug 1;172(2):547-57.
5) Complement activation and atherosclerosis.
Mol Immunol. 1999 Sep-Oct;36(13-14):949-55.
6) Niculescu, F., Hugo, F., Rus, H.G., Vlaicu, R. and Bhakdi, S., 1987. Quantitative evaluation of the terminal C5b-9
complement complex by ELISA in human atherosclerotic arteries. Clin. Exp. Immunol. 69, pp. 477¯483
7) Schmiedt, W., Kinscherf, R., Deigner, H.P., Kamencic, H., Nauen, O., Kilo, J. et al., 1998. Complement C6
deficiency protects against diet-induced atherosclerosis in rabbits. Arterioscler. Thromb. Vasc. Biol. 18, pp.
1790¯1795.
8) Jan Torzewski; CRP: evidence for an active role in the pathogenesis of atherosclerosis
BMC Meeting Abstracts: 2nd Hot Topic Workshop on CRP 2001, 1:012
9) Buono, C., Come, C. E., Witztum, J. L., Maguire, G. F., Connelly, P. W., Carroll, M., Lichtman, A. H. (2002).
Influence of C3 Deficiency on Atherosclerosis. Circulation 105: 3025-3031
10) Fitch JC, Rollins S, Matis L, Alford B, Aranki S, Collard CD, Dewar M, Elefteriades J, Hines R, Kopf G, Kraker P, Li
L, O'Hara R, Rinder C, Rinder H, Shaw R, Smith B, Stahl G, Shernan SK. Pharmacology and biological efficacy of a
recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery
bypass graft surgery with cardiopulmonary bypass. Circulation. 1999 Dec 21-28;100(25):2499-506.
References