Published online before print April 20, 2009, doi: 10.1161/CIRCULATIONAHA.108.830661
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(Circulation. 2009;119:2188-2195.)
© 2009 American Heart Association, Inc.
Molecular Cardiology |
Macrophage-Specific Expression of Mannose-Binding Lectin Controls Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice
From the Department of Surgery, Maastricht University Medical Centre and School for Nutrition and Metabolism, Maastricht, Netherlands (R.A.M., D.K., W.A.B.); Departments of Molecular Genetics (M.P.J.d.W., I.v.d.M., M.J.J.G.) and Pathology (M.V.H., M.J.G.), Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, Netherlands; and Institute for Molecular Cardiovascular Research, University Hospital, RWTH Aachen University, Aachen, Germany (C.W.).
Reprint requests to Dr W.A. Buurman, Department of General Surgery, Maastricht University Medical Centre, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, Netherlands. E-mail w.buurman{at}ah.unimaas.nl
Received October 22, 2008; accepted February 10, 2009.
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Abstract |
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Background— With consideration of the central role of the innate immune system in atherogenesis and mannose-binding lectin (MBL) as an innate regulator of immunity, the role of MBL in experimental and human atherosclerosis was assessed.
Methods and Results— With the use of immunohistochemistry and polymerase chain reaction, deposition and gene expression of MBL-A and -C were assessed in murine atherosclerosis from mice deficient for the low-density lipoprotein receptor (LDLR–/–) after 10 or 18 weeks of high-fat feeding. MBL was present and was produced in 10-week-old lesions, whereas deposition and gene expression were minimal after 18 weeks of high-fat feeding and absent in healthy vasculature. Interestingly, deposition of MBL-A and -C differed: MBL-A predominantly localized in upper medial layers, whereas MBL-C was found in and around intimal macrophages. To further study the role of local MBL production by monocytic cells in atherosclerosis, LDLR–/– mice with MBL-A and -C–/– monocytic cells were construed by bone marrow transplantation. Mice carrying MBL-A and -C double deficient macrophages had increased (30%) atherosclerotic lesions compared with wild-type controls (P=0.015) after 10 weeks of high-fat diet. Subsequently, analysis of MBL deposition and gene expression in advanced human atherosclerotic lesions revealed the presence of MBL protein in ruptured but not stable atherosclerotic lesions. Putatively in agreement with murine data, no MBL gene expression could be detected in advanced human atherosclerotic lesions.
Conclusions— These results are the first to show that MBL is abundantly present and locally produced during early atherogenesis. Local MBL expression, by myeloid cells, is shown to critically control development of atherosclerotic lesions.
Key Words: arteriosclerosis • cardiovascular diseases • immunology • molecular biology
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Introduction |
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Recently, the concept that different elements of the innate immune system mediate atherosclerosis has gained significance.1,2 In this respect, it is not surprising that complement components were detected in atherosclerotic lesions and shown to be of importance during atherogenesis from the earliest stages of plaque formation to the progression of advanced lesions.3,4
Clinical Perspective p 2195
Mannose-binding lectin (MBL) is a C-type or Ca2+-dependent lectin that can act as an opsonin and can activate complement through its own and evolutionary conserved lectin pathway.5 There is considerable variation in activating properties and plasma levels between individuals. These variations are caused by 3 first exon mutations (at codons 52, 54, and 57) and polymorphisms in the promoter region (at positions –550 [H/L] and –221 [X/Y]) of the structural gene (mbl2).6 Studies on the development of vascular diseases, including atherosclerosis in MBL-sufficient and -insufficient human subjects, suggested that the MBL C-type lectin influences vascular disease.7–13 Frequently, low MBL levels in MBL-deficient patients have been associated with an earlier disease onset or a more progressive disease course compared with their MBL-sufficient counterparts. However, opposing contributions by MBL to atherogenesis have been proposed as well. MBL-mediated modulation of Chlamydia pneumoniae infection, differences in complement activation, deficiencies in MBL-opsonizing capacities, and unknown sex-related differences may explain frequently observed associations between cardiovascular disease and mbl2 gene variations.7,10,14,15
The long-existing tenet that merely centrally produced complement components drive inflammatory reactions has recently been challenged.16–19 Locally synthesized complement proteins such as C1q and C3 greatly determine the innate immune response, contributing to, for example, ischemia/reperfusion-induced tissue damage.19 First reports suggest similar effects of locally produced complement components over the course of not only ischemia/reperfusion injury but also during development of atherosclerosis and neointima formation after arterial injury.17,18,20,21
The ostensible contradiction that remains regarding either a proatherogenic or antiatherogenic effect of MBL in atherosclerosis led us to investigate basic MBL characteristics over the course of atherogenesis in atherosclerosis-prone mice and human atherosclerotic lesions. Our data demonstrate the presence and distribution of MBL in experimental and human atherosclerotic lesions and provide compelling evidence for a controlling role of local myeloid-derived MBL expression in atherosclerosis development. The importance of MBL expression by myeloid cells in atherosclerosis development creates new insights into the role of this versatile immune regulatory protein during atherogenesis.
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Methods |
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For additional details, please see the online-only Data Supplement.
Mice and Preparation of Tissues
Mice were kept according to University of Maastricht animal facility regulations, and all experiments were approved by the local Animal Ethical Committee. Mice deficient for the low-density lipoprotein receptor (LDLR–/–) on a C57BL/6J background, 10 weeks old and weighing 25 g, were purchased at Jackson Laboratories (Bar Harbor, Me). Hearts and aortic arches were excised and embedded in OCT compound and frozen on dry ice and subsequently stored at –70°C.
Immunohistochemical Staining
Immunohistochemical stainings were performed with the use of a monoclonal antibody to murine macrophages (FA-11), which was kindly provided by Dr S. Gordon (Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom); to murine smooth muscle actin (1A4), which was purchased from Sigma (St Louis, Mo); to MBL-A (8G6) and MBL-C (14D12), all kindly provided by Hycult Biotechnology (Hbt, Uden, Netherlands); and to human MBL (ATLAS Antibodies, Stockholm, Sweden). Sirius red staining was performed to visualize collagen, and toluidine staining was used to visualize lesion structure. Colocalization studies were conducted by staining serial sections.
Reverse Transcription Polymerase Chain Reaction
Total RNA was extracted from differently staged murine atherosclerotic lesions and healthy vascular tissue with the use of the SV Total RNA isolation system (Promega Corporation, Madison, Wis). DNA contamination was eliminated by treating isolates with RQ1 RNase-Free DNase (Promega). Total RNA was reverse-transcribed with oligo(dT) primer and Moloney murine leukemia virus reverse transcriptase (Invitrogen, Carlsbad, Calif). cDNA synthesized from murine liver-derived total RNA isolate served as positive control sample for both MBL-A and MBL-C. The amount of amplified product was measured by the Nano-drop absorption measurement. The polymerase chain reaction conditions and visualization were described earlier.22
Bone Marrow Transplantation
Forty 9-week-old female littermate LDLR–/– mice on a C57BL/6 background (Jackson Laboratories) were put in filter-top cages. The mice received acidified water supplemented with neomycin (100 mg/L) and polymyxin B sulfate (60 000 U/L) starting the week before bone marrow transplantation until 5 weeks after bone marrow transplantation. Bone marrow was transplanted 2 weeks after antibiotic treatment was ended. One day before the actual transplantation, the mice were irradiated with a lethal dose of 10-Gy radiation. The bone marrow of 5 female wild-type (WT) mice (C57BL/6 from Taconic, Germantown, NY) and 5 female transgenic MBL-A and -C double knockout mice (C57BL/6, kindly provided by Dr S. Thiel, Institute of Medical Microbiology and Immunology, Aarhus University, Aarhus, Denmark) was collected. Bone marrow cells were harvested by flushing of the murine femur. For transplantation, 20 mice received WT bone marrow (WT-Tx), and 20 mice received transgenic bone marrow (KO-Tx). Bone marrow cells (106) were injected into the tail vein of each mouse.
Blood and Chimerism Analysis
Seven weeks after transplantation, the mice were put on a high-fat diet for 10 weeks. Chimerism was analyzed as described before,23 7 weeks after transplantation and before start of high-fat feeding. After 10 weeks of high-fat diet, blood was collected from the mice after overnight fasting to determine plasma cholesterol and plasma triglyceride concentration. Plasma cholesterol and triglycerides were determined with the use of the CHOD_PAP enzymatic essay kit (Roche, Basel, Switzerland) and GPO-Trinder kit (Sigma), respectively, according to the manufacturer’s guidelines. Peripheral blood leukocyte levels were analyzed after 5 weeks of high-fat feeding.
Atherosclerosis Assessment and Lesion Analysis
After 10 weeks of high-fat diet, the mice were killed. Atherosclerosis was analyzed as described before.23
Human Atherosclerotic Lesions
Atherosclerotic lesions (total n=17; stable [n=8] and ruptured [n=9]) were collected during surgical procedures (carotid eversion endarterectomy) from individuals suffering end-stage symptomatic occlusive vascular disease. Tissue specimens were fixated in formalin or immediately frozen in liquid nitrogen and stored until analysis at –80°C.
Statistical Analysis
Data are expressed as mean±SEM and were analyzed by unpaired 2-tailed Student t test. Data were analyzed with the use of Prism 4.01 for Windows (Graphpad Software, San Diego, Calif). A probability value <0.05 was considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agreed to the manuscript as written.
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Results |
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MBL Deposition in Developing Atherosclerotic Lesions
To assess the deposition of the murine MBL variants -A and -C, atherosclerotic lesions from LDLR–/– mice after 10 weeks of high-fat feeding were analyzed. The lesions displayed known characteristics with a considerable influx of macrophages into the subendothelial space (Figure 1A). Macrophages infiltrating the developing lesions were detected by macrophage-specific CD68 expression. Medial collagen filaments as well as the development of a thin fibrous cap covering the intima were shown by Sirius red staining (Figure 1B). Both murine MBL variants were widely present in atherosclerotic plaques at this stage after 10 weeks of Western diet feeding. Surprisingly, staining of the 2 MBL variants, with the use of serial sections, displayed different distribution patterns throughout 10-week lesions. MBL-A was frequently detected in the lower intimal layers directly above the media around the aortic sinus (Figure 1C). In addition, MBL-A was deposited on fibroblasts in the developing fibrous cap (Figure 1C, arrow). MBL-C, on the other hand, was detected solely in and around macrophages present in the intima (Figure 1D). Colocalization of MBL-A and -C occurred at sites of necrosis (as shown by the asterisk in Figure 1C and 1D). Healthy vasculature did not show staining for MBL-A (not shown) or MBL-C (Figure 1E).
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MBL Deposition in Advanced Atherosclerotic Lesions
Next, the course of MBL deposition in atherosclerosis after prolonged high-fat feeding (18 weeks) was studied. General characteristics of advanced lesions were similar to those observed in younger lesions, containing a substantial number of invading macrophages (Figure 2A). A more developed fibrous cap covered sizable parts of the advanced lesion (Figure 2A, indicated by arrows). Together these structures composed the better part of the advanced atherosclerotic plaque. In these lesions, MBL-A and -C staining was generally decreased compared with the 10-week fat-fed mice. Moreover, the distinct distribution of MBL-A in the upper medial layers directly under the plaque as well as on the fibrous cap covering the lesion was decreased or was no longer observed (Figure 2B). The typical distribution observed for MBL-C in and around CD68-positive macrophages, seen in early atherosclerosis, was similarly diminished (Figure 2C). After 18 weeks of high-fat feeding, MBL-A and -C localized predominantly to sites of necrosis that were positively identified by a pathologist specifically trained in the field of murine pathology (Figure 2B and 2C, indicated by asterisk).
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MBL-A and MBL-C Gene Expression in Atherosclerotic Lesions
To study local cellular MBL-A and -C production, MBL-A and -C gene expressions were assessed in total RNA, isolated from lesions obtained from LDLR–/– mice after various periods of high-fat feeding (10 or 18 weeks). Data were compared with data obtained from healthy vascular tissue. Figure 3 shows MBL-A and -C gene expression in 4 of 6 developing atherosclerotic lesions from LDLR–/– mice that were analyzed after 10 weeks of high-fat feeding. Surprisingly, only minimal MBL expression was detected in advanced lesions obtained from mice after 18 weeks of high-fat feeding. In agreement with the absence of cellular infiltrates in healthy vasculature, no MBL-A or -C mRNA was detectable. The data on MBL expression are supported by the immunohistochemical data that demonstrated abundant MBL presence in developing lesions, whereas only small amounts of MBL were detected in advanced atherosclerotic lesions, and no MBL was seen in healthy vascular tissue. Our reverse transcription polymerase chain reaction data suggest local MBL synthesis during early atherogenesis.
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Bone Marrow Transplantation
Considering the distribution of MBL and the MBL gene expression in developing atherosclerotic lesions, we hypothesized that macrophages might be a local source of MBL. Earlier, Seyfarth et al24 demonstrated mbl2 gene expression in differentiated and lipopolysaccharide-treated THP-1 cells, a human monocyte cell line. Studies performed at our laboratory confirmed these findings (unpublished data). To study the significance of macrophage-derived MBL transcription in atherosclerosis, a bone marrow transplantation was performed with the use of 2 groups of 20 atherosclerosis-prone mice (female, LDLR–/–) as recipients and WT or MBL-A and -C–/– donors. At the start of the high-fat feeding period, chimerism was similar in both groups (Table 1). At the end of the high-fat feeding period (10 weeks), total cholesterol and triglyceride plasma concentrations were statistically similar between groups (Table 1; P=0.16 and P=0.77, respectively). Total T-cell, B-cell, monocyte/macrophage, and granulocyte cell counts were similar between groups 11 weeks after bone marrow transplantation (Table 1). Interestingly, measurement of the total lesion area revealed a 30% increase in plaque size in LDLR–/– mice transplanted with MBL-A and -C–/– bone marrow (KO-Tx) after 10 weeks of high-fat feeding compared with LDLR–/– mice transplanted with WT bone marrow (WT-Tx) as the controls (Figure 4; *P=0.015). Figure 4 demonstrates microphotographs of representative atherosclerotic lesions from WT-Tx (Figure 4B) and KO-Tx (Figure 4C) mice. These data strongly suggest a determinative role for locally expressed MBL in the development of atherosclerosis.
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Immunohistochemical staining for MBL-A and -C demonstrated reduced levels of both murine MBL variants in KO-Tx atherosclerotic lesions compared with WT-Tx controls (asterisk, Figure 4D and Figure 4E). In KO-Tx lesions, MBL-C did not display its typical distribution around intimal macrophages (WT-Tx in Figure 4D and KO-Tx in Figure 4E inserts). In KO-Tx, MBL was predominantly present around areas of necrosis, thereby resembling MBL distribution observed in 18-week lesions, in which no local MBL-A and -C gene expressions were observed, indicating the plasma origin at this stage.
Human Atherosclerosis
Human atherosclerotic lesions were obtained during elective surgical procedures. The collected lesions were divided into 2 distinct groups, stable (n=8) and ruptured (n=9), as assessed by a skilled pathologist on a hematoxylin-eosin staining (data not shown). Paraffin sections stained for human MBL deposition showed, interestingly, MBL deposition in ruptured lesions (Figure 5). MBL deposits were located within the enlarged intima, along ill-defined necrotic segments of the atherosclerotic plaque. Cholesterol crystals (indicated by an asterisk in Figure 5), frequently observed within intimal lesions, did not colocalize with MBL deposits. In stable lesions, no human MBL staining was observed (Figure 5, insert). To determine the origin of human MBL in ruptured lesions, quantitative polymerase chain reaction analysis was performed on cDNA from total RNA isolates of both stable and ruptured atherosclerotic lesions. Interestingly, human MBL gene expression was observed neither in ruptured nor in stable end-stage human atherosclerotic lesions (Table 2). Similar to the murine data, these data indicate that MBL deposition detected in advanced stages of atherosclerosis might well be plasma derived.
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Discussion |
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The importance of complement in the development of atherosclerosis was first shown around the time that MBL was discovered in 197925 and has been corroborated since then. In 1998, 19 years after the detection of complement in atherosclerosis, a role for the lectin pathway was first proposed in atherogenesis.7 Since then, various contrasting reports suggested an intricate role for MBL in atherosclerosis. The apparently complex role of MBL during atherogenesis underscores the necessity for further study of the thus far poorly understood characteristics of MBL in atherosclerosis.26
Our results describe for the first time the deposition and distribution characteristics of MBL in early and advanced atherosclerotic lesions. More importantly, the data clearly suggest that the ability of myeloid cells to express MBL during atherogenesis influences atherosclerosis development.
The knowledge that the variation in plasma MBL levels in humans is regionally distributed around the world, with 
5% to 10% lacking functional MBL, has led to many studies that investigated MBL as a modifier of disease.6,27 Individuals that carry variant MBL alleles have an increased risk of infection and acute respiratory tract infections during early childhood, systemic lupus erythematosus, and meningococcal disease.28–31 In selected patient populations, well-characterized MBL gene variants have also been associated with an increased risk of thrombosis in systemic lupus erythematosus patients and heterosis in relation to mortality in patients in intensive care.32,33 Population-based studies addressing the role of MBL in atherosclerosis analyzed either MBL genotypes or resulting MBL serum levels in numerous different patient cohorts. From this work, it has been suggested that functional MBL might control atherosclerosis by ensuring the rapid clearance infectious agents, such as C pneumoniae, associated with atherosclerosis development.7,34 Moreover, there is an extensive search for the evolutionary advantage of low functional MBL plasma levels.35,36
To understand a possible role of MBL in atherogenesis, different known functions of MBL must be considered. Besides an effective regulator of complement activation, functional MBL can act as a potent opsonin of exogenous (infectious agents) or endogenous danger signals, such as late apoptotic and necrotic cells and cellular debris, which are associated with atherosclerosis development and plaque stability.37 Consequently, our results might indicate a differential role of MBL in atherogenesis. On the one hand, MBL expression during early atherogenesis may facilitate the rapid clearance of endogenous danger signals in the early atherogenic process, possibly constraining atherosclerosis development.38,39 On the other hand, increased levels of MBL expression in more advanced atherosclerotic lesions may have a proinflammatory role, as described earlier for coronary artery disease, myocardial infarction, and the risk of cardiac death in patients with type 2 diabetes and rheumatoid arthritis.15,40,41 Reduced levels of MBL expression, as demonstrated in advanced human and murine atherosclerotic lesions, may illustrate a futile effort to control complement activation, inflammation, and atherosclerosis progression. Interestingly, in its opsonizing capacity, MBL largely resembles the complement component C1q. Recently, C1q was found to reduce atherosclerosis development in atherosclerosis-prone LDLR–/– mice in comparison with C1q/LDLR–/– experimental controls. These findings were largely attributed to the ability of C1q to opsonize apoptotic cells and to facilitate phagocytic clearance in atherosclerotic lesions, a quality similarly observed for MBL.38,39 Moreover, the C1 complement complex has been shown to bind modified LDL, a major cause of inflammation in arterial vascular disease.42 Whether these observations also account for the contribution of MBL to atherosclerosis development will be a matter of future research.
Several other complement components have been associated with atherosclerosis development. Reduced complement activity, as seen in C3-, C5-, or C6-deficient mice or rabbit animal models, clearly affects atherosclerosis development.3,43–46 Atherosclerosis development in C3-deficient LDLR–/– as well as LDLR–/–/apolipoprotein E–/– mice was shown to be dependent on an altered lesion progression and lipid metabolism, resulting in increased lesion size compared with normal LDLR–/– and LDLR–/–/apolipoprotein E–/– control mice.43,44
Our findings suggest an important contribution of extrahepatic, myeloid-derived MBL gene expression to atherosclerosis development. MBL gene expression by myeloid-derived cells has been reported before.24 Moreover, the importance of extrahepatic MBL expression was clearly demonstrated from work on allogenic hemopoietic stem cell transplantations. Recipients of bone marrow from MBL variant donors had a >4-fold increased risk of serious infection compared with recipients of bone marrow derived from individuals without coding mutations in the mbl2 gene.47 The importance of extrahepatic complement, including MBL expression, in various pathologies led us to investigate the role of macrophage-specific MBL expression in atherosclerosis development. However, a systemic role of MBL in atherosclerosis should be further addressed by generation of MBL A/C–/––/– triple knockout animals. Such data could provide further insight into the role of circulating MBL in the epidemiological findings of MBL in vascular disease.14,15,40,41
Preliminary analysis of advanced human atherosclerotic lesions and MBL gene expression and MBL deposition supports our experimental murine data. Similar to observations in experimental atherosclerotic lesions, no MBL gene expression was observed in advanced human atherosclerotic plaques, suggesting a plasma origin of MBL during advanced stages of atherosclerosis development in mice and humans.
In conclusion, our data clearly demonstrate the deposition and local gene expression of MBL over the course of atherosclerosis development. Deposition and gene expression of MBL-A and -C were putatively attributed to a protective role for intimal macrophages in murine atherogenesis. The observation that MBL gene expression by myeloid cells controls lesion development is of major importance in unraveling cause and effect mechanisms between MBL and atherosclerosis development. Further studies on the role of versatile immunoregulatory proteins as complement proteins in atherosclerosis will undoubtedly generate new insights that increase our understanding of atherosclerosis as well as augment future treatment possibilities.
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Acknowledgments |
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The authors wish to thank Nicole Hoebers and Monique N. Vergouwe for their excellent technical assistance. Dr de Winther is an established investigator of the Netherlands Heart Foundation (2007T067).
Sources of Funding
This work was supported financially by the Netherlands Foundation of Scientific Research (ZonMw) grant 912.03.013 to Dr Buurman. Dr de Winther is financially supported by the Netherlands Foundation of Scientific Research VIDI grant 917.66.329.
Disclosures
Dr Buurman is a shareholder of the company Hbt that provided some of the monoclonal antibodies. These monoclonal antibodies, as used in this article, are commercially available worldwide. The authors have no further financial conflict of interest.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
2. Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868–874.[CrossRef][Medline] [Order article via Infotrieve]
3. Niculescu F, Rus H. The role of complement activation in atherosclerosis. Immunol Res. 2004; 30: 73–80.[CrossRef][Medline] [Order article via Infotrieve]
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; 172: 547–557.
5. Fujita T. Evolution of the lectin-complement pathway and its role in innate immunity. Nat Rev Immunol. 2002; 2: 346–353.[CrossRef][Medline] [Order article via Infotrieve]
6. Turner MW, Hamvas RM. Mannose-binding lectin: structure, function, genetics and disease associations. Rev Immunogenet. 2000; 2: 305–322.[Medline] [Order article via Infotrieve]
7. Madsen HO, Videm V, Svejgaard A, Svennevig JL, Garred P. Association of mannose-binding-lectin deficiency with severe atherosclerosis. Lancet. 1998; 352: 959–960.[CrossRef][Medline] [Order article via Infotrieve]
8. Best LG, Davidson M, North KE, MacCluer JW, Zhang Y, Lee ET, Howard BV, DeCroo S, Ferrell RE. Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians: the Strong Heart Study. Circulation. 2004; 109: 471–475.
9. Saevarsdottir S, Oskarsson OO, Aspelund T, Eiriksdottir G, Vikingsdottir T, Gudnason V, Valdimarsson H. Mannan binding lectin as an adjunct to risk assessment for myocardial infarction in individuals with enhanced risk. J Exp Med. 2005; 201: 117–125.
10. Rugonfalvi-Kiss S, Endresz V, Madsen HO, Burian K, Duba J, Prohaszka Z, Karadi I, Romics L, Gonczol E, Fust G, Garred P. Association of Chlamydia pneumoniae with coronary artery disease and its progression is dependent on the modifying effect of mannose-binding lectin. Circulation. 2002; 106: 1071–1076.
11. Hegele RA, Ban MR, Anderson CM, Spence JD. Infection-susceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area. J Investig Med. 2000; 48: 198–202.[Medline] [Order article via Infotrieve]
12. Limnell V, Aittoniemi J, Vaarala O, Lehtimaki T, Laine S, Virtanen V, Palosuo T, Miettinen A. Association of mannan-binding lectin deficiency with venous bypass graft occlusions in patients with coronary heart disease. Cardiology. 2002; 98: 123–126.[CrossRef][Medline] [Order article via Infotrieve]
13. Rugonfalvi-Kiss S, Dosa E, Madsen HO, Endresz V, Prohaszka Z, Laki J, Karadi I, Gonczol E, Selmeci L, Romics L, Fust G, Entz L, Garred P. High rate of early restenosis after carotid eversion endarterectomy in homozygous carriers of the normal mannose-binding lectin genotype. Stroke. 2005; 36: 944–948.
14. Hansen TK. Mannose-binding lectin (MBL) and vascular complications in diabetes. Horm Metab Res. 2005; 37 (suppl 1): 95–98.[CrossRef][Medline] [Order article via Infotrieve]
15. Keller TT, van Leuven SI, Meuwese MC, Wareham NJ, Luben R, Stroes ES, Hack CE, Levi M, Khaw KT, Boekholdt SM. Serum levels of mannose-binding lectin and the risk of future coronary artery disease in apparently healthy men and women. Arterioscler Thromb Vasc Biol. 2006; 26: 2345–2350.[CrossRef][Medline] [Order article via Infotrieve]
16. Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med. 2002; 8: 582–587.[CrossRef][Medline] [Order article via Infotrieve]
17. Cao W, Bobryshev YV, Lord RS, Oakley RE, Lee SH, Lu J. Dendritic cells in the arterial wall express C1q: potential significance in atherogenesis. Cardiovasc Res. 2003; 60: 175–186.
18. Yasojima K, Schwab C, McGeer EG, McGeer PL. Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001; 21: 1214–1219.
19. Farrar CA, Zhou W, Lin T, Sacks SH. Local extravascular pool of C3 is a determinant of postischemic acute renal failure. FASEB J. 2006; 20: 217–226.
20. Bhatia VK, Yun S, Leung V, Grimsditch DC, Benson GM, Botto MB, Boyle JJ, Haskard DO. Complement c1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol. 2007; 170: 416–426.
21. Shagdarsuren E, Bidzhekov K, Djalali-Talab Y, Liehn EA, Hristov M, Matthijsen RA, Buurman WA, Zernecke A, Weber C. C1-esterase inhibitor protects against neointima formation after arterial injury in atherosclerosis-prone mice. Circulation. 2008; 117: 70–78.
22. de Vries B, Walter SJ, Peutz-Kootstra CJ, Wolfs TG, van Heurn LW, Buurman WA. The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury. Am J Pathol. 2004; 165: 1677–1688.
23. Kanters E, Pasparakis M, Gijbels MJ, Vergouwe MN, Partouns-Hendriks I, Fijneman RJ, Clausen BE, Forster I, Kockx MM, Rajewsky K, Kraal G, Hofker MH, de Winther MP. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003; 112: 1176–1185.[CrossRef][Medline] [Order article via Infotrieve]
24. Seyfarth J, Garred P, Madsen HO. Extra-hepatic transcription of the human mannose-binding lectin gene (mbl2) and the MBL-associated serine protease 1–3 genes. Mol Immunol. 2006; 43: 962–971.[CrossRef][Medline] [Order article via Infotrieve]
25. Hollander W, Colombo MA, Kirkpatrick B, Paddock J. Soluble proteins in the human atherosclerotic plaque: with spectral reference to immunoglobulins, C3-complement component, alpha 1-antitrypsin and alpha 2-macroglobulin. Atherosclerosis. 1979; 34: 391–405.[CrossRef][Medline] [Order article via Infotrieve]
26. Hansson GK. Epidemiology complements immunology in the heart. Arterioscler Thromb Vasc Biol. 2006; 26: 2178–2180.
27. Holmskov U, Thiel S, Jensenius JC. Collections and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol. 2003; 21: 547–578.[CrossRef][Medline] [Order article via Infotrieve]
28. Super M, Thiel S, Lu J, Levinsky RJ, Turner MW. Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet. 1989; 2: 1236–1239.[Medline] [Order article via Infotrieve]
29. Koch A, Melbye M, Sorensen P, Homoe P, Madsen HO, Molbak K, Hansen CH, Andersen LH, Hahn GW, Garred P. Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood. JAMA. 2001; 285: 1316–1321.
30. Davies EJ, Snowden N, Hillarby MC, Carthy D, Grennan DM, Thomson W, Ollier WE. Mannose-binding protein gene polymorphism in systemic lupus erythematosus. Arthritis Rheum. 1995; 38: 110–114.[Medline] [Order article via Infotrieve]
31. Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M; Meningococcal Research Group. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet. 1999; 353: 1049–1053.[CrossRef][Medline] [Order article via Infotrieve]
32. Ohlenschlaeger T, Garred P, Madsen HO, Jacobsen S. Mannose-binding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. N Engl J Med. 2004; 351: 260–267.
33. Hellemann D, Larsson A, Madsen HO, Bonde J, Jarlov JO, Wiis J, Faber T, Wetterslev J, Garred P. Heterozygosity of mannose-binding lectin (MBL2) genotypes predicts advantage (heterosis) in relation to fatal outcome in intensive care patients. Hum Mol Genet. 2007; 16: 3071–3080.
34. Aittoniemi J, Fan YM, Laaksonen R, Janatuinen T, Vesalainen R, Nuutila P, Knuuti J, Hulkkonen J, Hurme M, Lehtimaki T. The effect of mannan-binding lectin variant alleles on coronary artery reactivity in healthy young men. Int J Cardiol. 2004; 97: 317–318.[CrossRef][Medline] [Order article via Infotrieve]
35. Fiane AE, Videm V, Lingaas PS, Heggelund L, Nielsen EW, Geiran OR, Fung M, Mollnes TE. Mechanism of complement activation and its role in the inflammatory response after thoracoabdominal aortic aneurysm repair. Circulation. 2003; 108: 849–856.
36. Dornelles LN, Pereira-Ferrari L, Messias-Reason I. Mannan-binding lectin plasma levels in leprosy: deficiency confers protection against the lepromatous but not the tuberculoid forms. Clin Exp Immunol. 2006; 145: 463–468.[CrossRef][Medline] [Order article via Infotrieve]
37. Bjorkerud S, Bjorkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol. 1996; 149: 367–380.[Abstract]
38. Nauta AJ, Castellano G, Xu W, Woltman AM, Borrias MC, Daha MR, van Kooten C, Roos A. Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells. J Immunol. 2004; 173: 3044–3050.
39. Ogden CA, deCathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, Henson PM. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med. 2001; 194: 781–795.
40. Troelsen LN, Garred P, Madsen HO, Jacobsen S. Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis. Arthritis Rheum. 2007; 56: 21–29.[CrossRef][Medline] [Order article via Infotrieve]
41. Hansen TK, Gall MA, Tarnow L, Thiel S, Stehouwer CD, Schalkwijk CG, Parving HH, Flyvbjerg A. Mannose-binding lectin and mortality in type 2 diabetes. Arch Intern Med. 2006; 166: 2007–2013.
42. Biro A, Thielens NM, Cervenak L, Prohaszka Z, Fust G, Arlaud GJ. Modified low density lipoproteins differentially bind and activate the C1 complex of complement. Mol Immunol. 2007; 44: 1169–1177.[CrossRef][Medline] [Order article via Infotrieve]
43. Buono C, Come CE, Witztum JL, Maguire GF, Connelly PW, Carroll M, Lichtman AH. Influence of C3 deficiency on atherosclerosis. Circulation. 2002; 105: 3025–3031.
44. Persson L, Boren J, Robertson AK, Wallenius V, Hansson GK, Pekna M. 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. 2004; 24: 1062–1067.
45. Schmiedt W, Kinscherf R, Deigner HP, Kamencic H, Nauen O, Kilo J, Oelert H, Metz J, Bhakdi S. Complement C6 deficiency protects against diet-induced atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 1998; 18: 1790–1795.
46. Patel S, Thelander EM, Hernandez M, Montenegro J, Hassing H, Burton C, Mundt S, Hermanowski-Vosatka A, Wright SD, Chao YS, Detmers PA. ApoE(–/–) mice develop atherosclerosis in the absence of complement component C5. Biochem Biophys Res Commun. 2001; 286: 164–170.[CrossRef][Medline] [Order article via Infotrieve]
47. Mullighan CG, Heatley S, Doherty K, Szabo F, Grigg A, Hughes TP, Schwarer AP, Szer J, Tait BD, Bik To L, Bardy PG. Mannose-binding lectin gene polymorphisms are associated with major infection following allogeneic hemopoietic stem cell transplantation. Blood. 2002; 99: 3524–3529.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.830661/DC1.
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