Atherosclerosis and Lipoproteins |
From the Department of Medical Biochemistry (L.P., M.P.), Wallenberg Laboratory for Cardiovascular Research (J.B.), and Research Center for Endocrinology and Metabolism (V.W.), The Sahlgrenska Academy at Göteborg University, Göteborg; and the Center for Molecular Medicine (A.-K.L.R., G.K.H.), Karolinska Institute, Stockholm, Sweden
Correspondence to Dr Marcela Pekna, Department of Medical Biochemistry, Göteborg University Box 440 S-405 30, Göteborg, Sweden. E-mail Marcela.Pekna{at}medkem.gu.se
| Abstract |
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Methods and Results Complement-deficient mice were crossed with mice deficient in both apolipoprotein E and the low-density lipoprotein receptor (Apoe/ LDLR/). The percent lesion area in the aorta at 16 weeks, determined by en face analysis, was 84% higher in C3/ mice than in controls (11.8%±0.4% versus 6.4%±0.8%, mean±SEM, P<0.00005). The C3/ mice also had 58% higher serum triglyceride levels (P<0.05) and a more proatherogenic lipoprotein profile, with significantly more low-density lipoprotein cholesterol and very-low-density lipoprotein triglycerides than control mice. The C3/ mice weighed 13% less (P<0.01) and had a lower body fat content (3.5%±1.0% versus 13.1%±3.0%, P<0.01). There were no differences between FB/ mice and controls.
Conclusions Complement activation by the classical or lectin pathway exerts atheroprotective effects, possibly through the regulation of lipid metabolism.
Deficiency in C3, but not in factor B, leads to more extensive atherosclerotic lesions, increased hyperlipidemia, and reduced body fat in Apoe/ LDLR/ mice. Complement activation by the classical or lectin pathway exerts atheroprotective effects, possibly through the regulation of lipid metabolism.
Key Words: atherosclerosis complement C3 factor B hyperlipidemia
| Introduction |
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C3-derived peptides have been implicated in the regulation of lipid metabolism. C3a and C3ades-Arg, a peptide formed when the C-terminal arginine is removed from C3a by carboxypeptidase N, can act as acylation-stimulating protein (ASP).1 ASP has been implicated in adipose tissue function and maintenance of metabolic homeostasis.2 ASP and C3a increase fat storage in adipocytes through increased triglyceride synthesis35 and decreased intracellular lipolysis.5 Mice that are deficient in C3, and therefore unable to synthesize ASP, have delayed triglyceride clearance,68 which can be normalized by administration of ASP.7,9,10 However, Wetsel et al did not detect any impaired ability of C3/ mice to clear triglycerides and free fatty acids from the circulation after an oral fat load.11 FB/ mice are viable and fertile and have no overall abnormalities of the immune system.12,13 The effect of FB deficiency on adipose tissue and blood lipid profiles has thus far not been studied.
Atherosclerosis is characterized by an inflammatory response to the accumulation of subendothelial lipids, and there is evidence that the activated complement system is involved in atheroma formation.14 Complement components and activation products have been identified in the walls of diseased vessels,1518 and mRNAs of complement components are expressed in atherosclerotic plaques. However, the role of complement inhibitors is more controversial.19,20 The degree of TCC deposition correlates with the severity of arterial damage.21,22 In rabbits, TCC and lipid colocalize in the aortic tunica intima.23 Similarly, in human lesions, TCC colocalizes with enzymatically modified lipoproteins.24 Lipoprotein particles in vitro as well as modified lipoproteins are also potent activators of complement.25,26 The severity of cholesterol-induced atherosclerosis is reduced in C6-deficient rabbits.27,28 In apolipoprotein E-deficient (Apoe/) mice, the absence of C5 does not affect atheroma formation,29 whereas aortic lipid-positive lesional size is reported to be greater in C3/ low-density lipoprotein receptor-deficient (LDLR/) mice than in controls.30
To assess the role of the early components of the complement system in the pathogenesis of atherosclerosis and the regulation of plasma lipids, we crossed Apoe/ LDLR/ mice31 with C3/32 or FB/ mice.12 C3/ mice cannot activate the complement cascade beyond the formation of the C3-convertase of the classical/lectin pathway, and FB/ mice are unable to activate the alternative pathway. The use of these 2 complement-deficient strains enabled us to assess the relative roles of these activation pathways.
| Methods |
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Processing and Analysis of the Aorta
The aortic root was processed and quantified as described.33 Sections were obtained 100, 200, 300, and 400 µm from the origin of the aortic valve cusps and stained with Oil Red O (Sigma-Aldrich, St. Louis, Mo). The aorta was prepared and analyzed en face as described.34 In brief, the aortas were pinned on wax plates and stained with Sudan IV. The extent of atherosclerosis was expressed as the percentage of the aortic surface covered by lesions. The results from control Apoe/ LDLR/ mice fed normal chow were comparable with data published for Apoe/ and LDLR/ mice fed a high-cholesterol diet.30,33
Serum Lipid Analyses
Blood for lipid analyses was collected before perfusion of the animals and allowed to clot, and the serum was stored at 20°C. Cholesterol and triglycerides were analyzed with a Konelab 30 automated analyzer (Thermo Electron Clinical Chemistry & Automation Systems) using the reagents triglycerides 981786 and cholesterol 981773, as recommended by the manufacturer. The lipid distribution in plasma lipoprotein fractions was assessed by fast-performance liquid chromatography gel filtration with a Superose 6 HR 10/30 column (Pharmacia, Uppsala, Sweden).35
Postprandial Triglyceride Clearance
Postprandial triglyceride clearance was measured as described.7 Blood samples were collected before and 1, 2, 3, 4, and 6 hours after oral administration of olive oil.
Body Fat Measurement
Body fat content was measured in vivo by dual-energy x-ray absorptiometry (DXA).36
Serum Anti-LDL Antibody Measurements
Specific antibodies to malondialdehyde (MDA)-modified low-density lipoprotein (LDL) were quantified by enzyme-linked immunosorbent assay.37
Histological Evaluation and Immunohistochemistry
Aortic root sections were stained with hematoxylin and erythrosine or Masson trichrome (Bio-Optica, Milan, Italy) to identify foam cells, fibrosis, cholesterol clefts, acellular areas, and fibrous cap in atherosclerotic plaques. For immunohistochemistry, sections were fixed in acetone, incubated with 1% bovine serum albumin in phosphate-buffered saline-Tween, and stained with MOMA-2 (Serotec, Oxford, UK) and
-smooth muscle actin (EPOS; Dako A/S, Glostrup, Denmark) antibodies. The MOMA-2 antibody was detected by biotin-conjugated rabbit antiserum against rat immunoglobulins (Dako A/S) followed by ABC Vectastain Elite kit (Vector Laboratories, Burlingame, Calif) and visualized with 3, 3'-diaminobenzidine tetrahydrochloride (Sigma).
Statistical Analysis
The results are presented as mean±SEM. The data were analyzed by unpaired t test. Repeated-measures analysis of variance was used to analyze the postprandial triglyceride clearance data. Differences were considered statistically significant at P<0.05.
| Results |
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Atherosclerotic Lesions Are Qualitatively Similar in C3/ and Control Mice
Morphological examination of aortic root sections at 16 weeks revealed lesions in all mice, ranging from fatty streaks composed of foam cells to advanced fibrofatty lesions covered by fibrous cap. At 26 weeks, the lesions often covered the whole inner circumference of the vessel, and all were exclusively of the fibroatheromatous type, the majority with large acellular areas, a fibrous cap of varying thickness, and extensive necrosis. No difference in plaque progression was noted between groups. As shown by MOMA-2 staining, macrophages were the predominant cell type in all lesions, although lesions in the older mice were less cellular. The extent and distribution of MOMA-2 staining were similar in complement-deficient mice and controls. Fibrous caps, visualized by
-smooth muscle actin immunostaining, were observed in all sections analyzed, with no difference between the experimental groups (Figure I, available online at http://atvb.ahajournals.org).
C3 Deficiency Increases Serum Triglycerides and Alters Plasma Lipoprotein Profiles
In C3/ mice, serum triglyceride levels were 58% higher than in controls at 16 weeks (6.8±0.9 versus 4.3±0.4 mmol/L, P<0.05) and 79% higher at 26 weeks (8.4±1.3 versus 4.4±0.6 mmol/L, P<0.05) (Figure 3A). C3 deficiency did not affect serum cholesterol levels at any age (Figure 3B). Serum cholesterol and triglyceride levels were similar in FB/ and control mice (Figure 3C and 3D). Superose 6 chromatography of pooled plasma showed a more proatherogenic lipoprotein profile in C3/ mice, with significantly more LDL cholesterol and very-low-density lipoprotein (VLDL) triglycerides than controls at both 16 and 26 weeks (Figure 4).
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C3/ Mice Have Normal Postprandial Triglyceride Clearance
Next, we determined if the increased serum lipid levels of the C3/ mice could be explained by an aberrant postprandial lipid clearance. No differences in serum triglyceride levels were observed after an oral fat load in 21-week-old C3/ (n=4) and control mice (n=5) (not shown).
C3 Deficiency Reduces Body Weight and Body Fat
Compared with controls, C3/ mice weighed 13% less at 16 weeks (34.2±0.96 versus 38.8±1.29 g, n=17/group, P<0.01) and 22% less at 26 weeks (34.7±1.12 g, n=10, versus 42.3±1.93 g, n=11, P<0.005). There were no differences in body weight between the FB/ and control mice at either time point. As shown by DXA analysis of body composition, C3/ mice had approximately two-thirds less body fat than controls at 16 weeks (3.5%±1.0% versus 13.1%±3.0%, P<0.01) and 26 weeks (2.8%±0.7% versus 9.3±1.9%, P<0.01) (Figure 5).
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C3 Deficiency Does Not Alter Anti-MDAModified-LDL Antibody Titers
To determine if the effect of complement on atherogenesis could result from changes in B-cell-associated protective immunity,38 we assessed the immunoglobulin M (IgM) and immunoglobulin G (IgG) isotypes of autoantibodies against MDA-modified LDL. There were no differences in anti-MDA-LDL IgM or IgG titers between C3/ mice and controls (not shown).
| Discussion |
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In our study, histopathological and immunohistochemical analyses of the aortic root showed no qualitative differences in lesion morphology between C3/ and control mice. However, we cannot exclude that the C3 deficiency may have resulted in morphological differences such as reduced collagen and smooth muscle cell content in the lesions distal to the aortic root as reported for the C3/ LDLR/ mice.30 In addition, the strong atherogenic drive in the Apoe/ LDLR/ mice might have masked a milder anti-atherogenic effect of the complement system in the vascular wall and might also explain why C3/ and control mice had lesions of similar size at 26 weeks. Given the possible role of antibodies in atheroprotective immunity,33,3840 we analyzed sera from C3/ and control mice for antibodies against MDA-LDL. No differences in antibody levels were detected, indicating that the increased atherosclerosis in C3/ Apoe/ LDLR/ mice is not likely a result of impairments in B-cell-associated protective immunity or protective antibody production.
C3/ mice also had a more atherogenic plasma lipoprotein profile than controls, with elevated serum triglyceride levels, increased VLDL triglycerides, and increased LDL cholesterol. In addition, the C3/ mice weighed less and had a lower body fat mass. The latter findings are in line with recent reports showing that C3/ mice had reduced body weight and fat mass and were resistant to weight gain on a high-fat diet, despite increased food intake.8,41 These phenotypic abnormalities may reflect reduced triglyceride synthesis by adipocytes because of the absence of C3-derived ASP, as proposed by Sniderman et al.42 Thus, the absence of ASP leads to a more atherogenic lipoprotein profile and increased atherosclerosis. Cianflone et al2 suggested that discrepancies in plasma lipid levels and triglyceride clearance in C3/ mice in different reports68,11 could be explained by the influence of genetic background, resulting in differences in insulin sensitivity, lipoprotein lipase activity, or triglyceride synthesis by adipose tissue.
In contrast to the results in C3/ mice, the extent of atherosclerosis, serum triglyceride levels, and body weight were not significantly different in FB/ Apoe/ LDLR/ mice and controls. Because C3, FB, and factor D are produced in adipose tissue, ASP is believed to be generated by the alternative pathway of complement activation. In support of this possibility, there is no evidence that adipocytes produce C2, an essential component of the classical and lectin pathways.43,44 Although FB/ mice have normal C3 levels, they cannot generate ASP through proteolytic cleavage mediated by FB and factor D. Our findings suggest that the alternative pathway is not required for C3-mediated control of energy storage and energy use and that ASP is generated by other mechanisms, such as activation of the classical and/or lectin pathway locally in adipose tissue or in the circulation. Interestingly, genes encoding proteins of the classical pathway are expressed in human adipose tissue.45
An alternative explanation for the phenotype of the C3/ mice is the absence of uncleaved C3. One possibility worth exploring is the capacity of C3(H2O) to bind to the C3a/ASP receptor C5L246 and to exhibit the functions ascribed to ASP. C3(H2O)the product of spontaneous hydrolysis of the internal thioester bond of the native C3 moleculeis conformationally and functionally similar to C3b. It can bind FB and form the C3 convertase of the alternative pathway. However, it still contains the C3a fragment4749 and therefore could, theoretically, act like ASP.
En face assessment of the whole aorta revealed a significant difference in percent lesion area between C3/ and control mice at 16 weeks of age that were not seen by analysis of aortic root sections. Babaev et al also reported a loss of correlation between lesion areas determined by these two methods when lesions in the proximal aorta became complicated.50 Thus, for detecting effects on disease development, en face analysis of the percent lesion area appears to be a more sensitive method than measuring plaque area in sections from the aortic root, at least in the Apoe/ LDLR/ model.
| Conclusion |
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| Acknowledgments |
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The authors thank Kristina Skålén, Maria Garcia, Anna Berndtsson, Lisbeth Lindgren, and Ingrid Törnberg for technical help. The work was supported by grants from The Swedish Medical Research Council (Projects 13470 and 6816), King Gustaf V 80th Anniversary Foundation, The Swedish Heart-Lung Foundation, The Swedish Society of Medicine, The Swedish Society for Medical Research, and Sigurd and Elsa Goljes Foundation.
| Footnotes |
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Received December 22, 2003; accepted March 22, 2004.
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A. M Carter Inflammation, thrombosis and acute coronary syndromes Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 113 - 121. [Abstract] [PDF] |
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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] |
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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] |
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