Published Online
on June 3, 2002

A more recent version of this article appeared on June 25, 2002

This Article Full Text (PDF) All Versions of this Article: 105/25/3025    most recent 01.CIR.0000019584.04929.83v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buono, C. Articles by Lichtman, A. H. Search for Related Content PubMed Articles by Buono, C. Articles by Lichtman, A. H. Related Collections Calcium cycling/excitation-contraction coupling Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors

Submitted on February 25, 2002
Revised on April 3, 2002
Accepted on April 8, 2002

Influence of C3 Deficiency on Atherosclerosis

Chiara Buono MD, Carolyn E. Come BA, Joseph L. Witztum MD, Graham F. Maguire BSc, Philip W. Connelly PhD, Michael Carroll PhD, and Andrew H. Lichtman MD, PhD^*

From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School (C.B., C.C., A.H.L.) and Center for Blood Research and Department of Pediatrics, Harvard Medical School (M.C.), Boston, Mass; Department of Medicine (J.L.W.), University of California, San Diego, La Jolla, Calif; and J. Alick Little Lipid Research Laboratory (G.M., P.W.C.), St Michael's Hospital, Toronto, Ontario, Canada.

^* To whom correspondence should be addressed. E-mail: alichtman{at}rics.bwh.harvard.edu.

Background—The influence of complement activation on atherosclerosis is not well understood. The purpose of this study was to examine the effects of C3 deficiency on the extent and phenotype of atherosclerosis.

Methods and Results—Aortic atherosclerosis was analyzed in low-density lipoprotein receptor (ldlr)/C3-deficient mice (ldlr^-/-C3^-/-) and ldlr^-/-C3^+/- littermate control mice after 15 weeks on a 1.25% (wt/wt) cholesterol diet. Serum lipoprotein profiles and immunoglobulin levels were not significantly different between the 2 experimental groups. The lipid-positive en face lesional area in thoracic and abdominal aorta was greater in C3-deficient mice than in control mice (3.9% versus 2.1%, median, P=0.0076). Similarly, the lipid-positive area in aortic arch sections was greater in C3-deficient mice than in controls (0.04 mm² versus 0.02 mm², median, P=0.0089). Analysis of aortic arch sections showed greater lesional macrophage content in C3-deficient versus control mice (8.24±1.36% versus 5.9±1.63% intimal area, mean±SEM, P=0.003), less smooth muscle cell content in C3-deficient versus control mice (0.06±0.05% versus 0.92±0.32% intimal area, mean±SEM, P<0.0001), and less collagen content in C3-deficient versus control mice (0.52±1.26% versus 11±10.43% intimal area, mean±SEM, P=0.008).

Conclusions—The maturation of atherosclerotic lesions beyond the foam cell stage is strongly dependent on an intact complement system.

Key words: atherosclerosis • complement • inflammation

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]

				M. J. Lewis, T. H. Malik, M. R. Ehrenstein, J. J. Boyle, M. Botto, and D. O. Haskard Immunoglobulin M Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, August 4, 2009; 120(5): 417 - 426. [Abstract] [Full Text] [PDF]

				R. A. Matthijsen, M. P.J. de Winther, D. Kuipers, I. van der Made, C. Weber, M. V. Herias, M. J.J. Gijbels, and W. A. Buurman Macrophage-Specific Expression of Mannose-Binding Lectin Controls Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, April 28, 2009; 119(16): 2188 - 2195. [Abstract] [Full Text] [PDF]

				E. Shagdarsuren, K. Bidzhekov, Y. Djalali-Talab, E. A. Liehn, M. Hristov, R. A. Matthijsen, W. A. Buurman, A. Zernecke, and C. Weber C1-Esterase Inhibitor Protects Against Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice Circulation, January 1, 2008; 117(1): 70 - 78. [Abstract] [Full Text] [PDF]

				F. Verdeguer, C. Castro, M. Kubicek, D. Pla, M. Vila-Caballer, A. Vinue, F. Civeira, M. Pocovi, J. J. Calvete, and V. Andres Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation Cardiovasc Res, November 1, 2007; 76(2): 340 - 350. [Abstract] [Full Text] [PDF]

				G. Jonsson, A. G. Sjoholm, L. Truedsson, A. A. Bengtsson, J. H. Braconier, and G. Sturfelt Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency Rheumatology, July 1, 2007; 46(7): 1133 - 1139. [Abstract] [Full Text] [PDF]

				J. K. Pai, J. E. Manson, K. M. Rexrode, C. M. Albert, D. J. Hunter, and E. B. Rimm Complement factor H (Y402H) polymorphism and risk of coronary heart disease in US men and women Eur. Heart J., June 1, 2007; 28(11): 1297 - 1303. [Abstract] [Full Text] [PDF]

				D. R. Anderson, J. M. Tsutsui, F. Xie, S. J. Radio, and T. R. Porter The role of complement in the adherence of microbubbles to dysfunctional arterial endothelium and atherosclerotic plaque Cardiovasc Res, February 1, 2007; 73(3): 597 - 606. [Abstract] [Full Text] [PDF]

				V. K. Bhatia, S. Yun, V. Leung, D. C. Grimsditch, G. M. Benson, M. B. Botto, J. J. Boyle, and D. O. Haskard Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Am. J. Pathol., January 1, 2007; 170(1): 416 - 426. [Abstract] [Full Text] [PDF]

				G. K. Hansson Epidemiology Complements Immunology in the Heart Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2178 - 2180. [Full Text] [PDF]

				R. Somani, P. J. Grant, K. Kain, A. J. Catto, and A. M. Carter Complement C3 and C-Reactive Protein Are Elevated in South Asians Independent of a Family History of Stroke Stroke, August 1, 2006; 37(8): 2001 - 2006. [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]

				A. M Carter Inflammation, thrombosis and acute coronary syndromes Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 113 - 121. [Abstract] [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]

				P. S. Heeger, P. N. Lalli, F. Lin, A. Valujskikh, J. Liu, N. Muqim, Y. Xu, and M. E. Medof Decay-accelerating factor modulates induction of T cell immunity J. Exp. Med., May 16, 2005; 201(10): 1523 - 1530. [Abstract] [Full Text] [PDF]

				J. Li, P. C. Pircher, I. G. Schulman, and S. K. Westin Regulation of Complement C3 Expression by the Bile Acid Receptor FXR J. Biol. Chem., March 4, 2005; 280(9): 7427 - 7434. [Abstract] [Full Text] [PDF]

				G. S. Getz Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis J. Lipid Res., January 1, 2005; 46(1): 1 - 10. [Abstract] [Full Text] [PDF]

				A. Recinos III, B. K. Carr, D. B. Bartos, I. Boldogh, J. R. Carmical, L. M. Belalcazar, and A. R. Brasier Liver gene expression associated with diet and lesion development in atherosclerosis-prone mice: induction of components of alternative complement pathway Physiol Genomics, September 16, 2004; 19(1): 131 - 142. [Abstract] [Full Text] [PDF]

				Z.-H. Lin, N. Fukuda, X.-Q. Jin, E.-H. Yao, T. Ueno, M. Endo, S. Saito, K. Matsumoto, and H. Mugishima Complement 3 Is Involved in the Synthetic Phenotype and Exaggerated Growth of Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats Hypertension, July 1, 2004; 44(1): 42 - 47. [Abstract] [Full Text] [PDF]

				L. Persson, J. Boren, A.-K. L. Robertson, V. Wallenius, G. K. Hansson, and M. Pekna Lack of Complement Factor C3, but Not Factor B, Increases Hyperlipidemia and Atherosclerosis in Apolipoprotein E-/- Low-Density Lipoprotein Receptor-/- Mice Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1062 - 1067. [Abstract] [Full Text] [PDF]

				S. Bhakdi, M. Torzewski, K. Paprotka, S. Schmitt, H. Barsoom, P. Suriyaphol, S.-R. Han, K. J. Lackner, and M. Husmann Possible Protective Role for C-Reactive Protein in Atherogenesis: Complement Activation by Modified Lipoproteins Halts Before Detrimental Terminal Sequence Circulation, April 20, 2004; 109(15): 1870 - 1876. [Abstract] [Full Text] [PDF]

				A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF]

				G.M. Hirschfield and M.B. Pepys C-reactive protein and cardiovascular disease: new insights from an old molecule QJM, November 1, 2003; 96(11): 793 - 807. [Abstract] [Full Text] [PDF]

				W. Koenig C-reactive protein and cardiovascular risk: an update on what is going on in cardiology Nephrol. Dial. Transplant., June 1, 2003; 18(6): 1039 - 1041. [Full Text] [PDF]

				R. Oksjoki, H. Jarva, P. T. Kovanen, P. Laine, S. Meri, and M. O. Pentikainen Association Between Complement Factor H and Proteoglycans in Early Human Coronary Atherosclerotic Lesions: Implications for Local Regulation of Complement Activation Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 630 - 636. [Abstract] [Full Text] [PDF]