Published online before print March 27, 2006, doi: 10.1161/CIRCULATIONAHA.104.513820
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(Circulation. 2006;113:1702-1707.)
© 2006 American Heart Association, Inc.
Vascular Medicine |
Abdominal Aortic Aneurysm Is Associated With High Serum Levels of Tenascin-X and Decreased Aneurysmal Tissue Tenascin-X
From the Department of Dermatology (M.C.Z., J.S.), Nijmegen Centre for Molecular Life Sciences, and the Departments of Endocrinology (A.C.T.M.P., M.d.H.), Epidemiology and Biostatistics (M.d.H.), and Surgery (J.A.v.d.V.,), Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; and the Departments of Internal Medicine (S.G.) and Surgery (S.K.), TweeSteden Hospital, Tilburg, the Netherlands.
Correspondence to Martin den Heijer, Department of Endocrinology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail M.denHeijer{at}endo.umcn.nl
Received June 1, 2004; de novo received October 12, 2004; revision received January 20, 2006; accepted January 27, 2006.
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Abstract |
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Background— Tenascin-X is a large extracellular matrix protein that is abundantly expressed in several connective tissues. A 140-kDa C-terminal fragment of tenascin-X is present in human serum. Complete deficiency of tenascin-X is associated with Ehlers-Danlos syndrome, and these patients show major connective tissue alterations in their skin, as well as blood vessel fragility. In this study, we investigated whether tenascin-X is present in normal human aorta and abdominal aortic aneurysm (AAA) tissues and whether an association exists between serum tenascin-X levels and AAA.
Methods and Results— Five normal aortas and 5 AAA tissues were immunostained for tenascin-X and elastin. Tenascin-X was present throughout the entire aorta and was especially abundant near the elastic lamellae, whereas tenascin-X expression was strongly decreased in AAA tissue. Measurement of tenascin-X serum concentration by enzyme-linked immunosorbent assay (ELISA) in 87 AAA patients and 86 controls demonstrated an increasing risk for AAA with increasing tenascin-X serum concentrations. After adjustment for established risk factors, tenascin-X serum concentrations in the highest quartile were associated with a 5-fold increase in risk of AAA (odds ratio, 5.3; 95% confidence interval, 2.0 to 13.8).
Conclusions— Tenascin-X expression is markedly decreased in AAA tissue, and AAA is associated with high serum concentrations of tenascin-X.
Key Words: aneurysm • collagen • extracellular matrix • pathology • risk factors
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Introduction |
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Human abdominal aortic aneurysm (AAA) is a common disease in the elderly, accounting for 1% to 2% of all deaths in men in Western countries. Risk factors for the development of AAA include smoking, male sex, advanced age, family history, and hypertension.1 Although the exact pathogenesis remains unknown, changes in the biosynthesis and proteolysis of extracellular matrix proteins have been implicated in the development of AAA (for reviews, see Grange et al,2 Macsweeney et al,3 and Marian4). Several studies have reported that increased proteolytic activity of matrix metalloproteinases causes destruction of the connective tissue of the vascular wall.5–8 Studies on human and experimental AAAs have shown degradation of the elastic lamellae, which are designed to last a lifetime, and greatly enhanced collagen production. These processes result in altered mechanical properties of the aortic wall and ultimately, aneurysmal dilatation.9–12 The importance of extracellular matrix proteins in the pathogenesis of AAA is further emphasized by the fact that patients with mutations in the fibrillin-1 or COL3A1 gene commonly develop AAA at an early age.13
Clinical Perspective p 1707
Tenascin-X is a 450-kDa extracellular matrix protein that is broadly expressed in the myocardium, skin, tendons, and skeletal muscle. Tenascin-X expression is also associated with blood vessels in most tissues.14,15 The exact extracellular localization and cellular source of tenascin-X in blood vessels remain to be investigated. Besides its expression in various connective tissues, tenascin-X is readily detected in human serum as a 140-kDa protein, probably resulting from alternative splicing or proteolytic cleavage.16 The level of serum tenascin-X likely reflects its rate of synthesis in the connective tissues, because individuals heterozygous for a tenascin-X null allele express 
50% of the mean of control subjects in their sera.17 Interestingly, a deficiency of tenascin-X causes a new type of connective tissue disease, Ehlers-Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and fragility of blood vessels.16 Skin biopsies of these individuals show severe abnormalities in elastic fibers and collagen, which are also principal components of blood vessels.18
The aim of the present study was 2-fold: First, we wanted to examine the presence and localization of tenascin-X in normal aortas and AAAs, and second, we wanted to investigate whether an association exists between AAA and tenascin-X expression.
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Methods |
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Study Population and Specimen Collection
Normal aorta samples (n=5) were obtained from archival postmortem material, and AAA samples (n=5) were obtained from patients undergoing surgery for their aneurysms. For determination of tenascin-X serum levels, sera were collected from AAA patients and control subjects and stored at –20°C. Storage did not affect the serum tenascin-X assay. From August 1996 to September 1997, all patients who presented with AAA at the TweeSteden Hospital, Tilburg, were invited to participate in this study. The patients included were invited to bring a friend or neighbor of the same age and sex to serve as a control subject. Identification of subjects with AAA was done by the Department of Vascular Surgery and included patients who survived a ruptured aorta, patients with complaints of an AAA, and patients for whom the diagnosis was made through ultrasonography performed for other reasons. Conventional open surgery was performed in all patients. In the group of patients who did not undergo surgery, serial ultrasonography was performed for clinical follow-up; in the control group, ultrasonography was performed to exclude AAA. Abdominal aortic investigations were performed with an Acuson XP10 with a 4-MHz convex transducer (Acuson Corporation, Mountain View, Calif). Imaging was performed by an experienced investigator. The maximum diameter of the abdominal aorta was identified through longitudinal scanning from the diaphragm to the aortic bifurcation. Maximum diameter of the infrarenal aorta was measured in anteroposterior views during systole. The study population consisted of 87 individuals with an AAA (ultrasonographically proven anteroposterior infrarenal aortic diameter >30 mm) and 86 individuals who participated as a control group. Baseline characteristics of patients with AAA and control individuals are shown in Table 1. The methods by which interview data were obtained and blood samples were collected have been described elsewhere.19 In brief, all participants completed a questionnaire about medical history and medication use. Peripheral vascular disease was defined either as a history of claudicatio intermittens20 or when a person had undergone surgery because of claudicatio intermittens. A blood sample was taken for determination of concentration of tenascin-X. Informed consent was obtained, and all study protocols were approved by the local ethics committee.
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Immunolocalization Studies
Cryosections (6 µm) of normal human aortas and AAAs were prepared, placed on 3-aminopropyltriethoxysilane–coated slides (Sigma, St. Louis, Mo), and fixed for 10 minutes in acetone. After preincubation with 20% normal goat serum (Dako, Glostrup, Denmark), the slides were incubated with guinea pig anti–tenascin-X (1:1000 dilution). Then the sections were incubated with biotinylated anti–guinea pig IgG, followed by either peroxidase-conjugated avidin-biotin complex and aminoethylcarbazol (both from Vector Labs, Burlingame, Calif) as the chromogenic substrate or fluorescein isothiocyanate–labeled anti–guinea pig IgG (Dako, Copenhagen, Denmark). Appropriate controls with preimmune serum and omission of the primary antibody were performed. For colocalization studies, monoclonal anti-elastin (BA-4, Sigma) was used, followed by AlexaFluor 594–labeled anti-mouse IgG (Molecular Probes, Leiden, The Netherlands).
Enzyme-Linked Immunosorbent Assay for Measurement of Tenascin-X Levels
Tenascin-X concentrations in human sera were measured with a sandwich-type enzyme-linked immunosorbent assay (ELISA), as described previously.16 In short, microtiter plates were coated with rabbit anti–tenascin-X (1 µg/mL in phosphate-buffered saline) for antigen capture. Microtiter plates were blocked with 1% bovine serum albumin before dilutions of the samples and the standard (a 100-kDa recombinant fragment of tenascin-X) were applied. As a second antibody, guinea pig anti–tenascin-X antiserum (dilution 1:1000) was used, followed by biotinylated goat anti–guinea pig immunoglobulin and peroxidase-conjugated avidin-biotin complex (Vector Labs) for antigen detection. Finally, o-phenylenediamine dihydrochloride (Pierce, Rockford, Ill) was added as a chromogenic substrate. The reaction was stopped by addition of 4N H2SO4, and absorbance was measured at 492 and 655 nm. Tenascin-X concentrations were read from a calibration curve of recombinant tenascin-X (ranging from 0.5 ng/mL to 1 µg/mL). The coefficient of variation of repeated measurements was 5.7%.
Statistical Analysis
To determine the influence of tenascin-X levels on the risk of development of AAA, we stratified tenascin-X levels into quartiles and calculated odds ratios (ORs) and 95% confidence intervals (CIs) with the use of SPSS (SPSS, Chicago, Ill) software. Logistic regression was used to adjust for potential confounders.
The authors had full access to the data and take full responsibility for their integrity. All authors have read and agreed to the manuscript as written.
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Results |
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To study whether tenascin-X is present in normal aortic tissue and whether this expression pattern is altered in AAA samples, we performed immunolocalization studies. In normal aortas, tenascin-X was present throughout the entire vascular wall (Figure, A). Tenascin-X expression appeared particularly closely associated with the elastic lamellae in the aortic media (Figure, B). In AAA, a completely different architecture was found. The number of elastic fibers was greatly decreased, and the elastic fiber morphology was disturbed (not shown). Tenascin-X expression was markedly decreased in AAAs compared with normal aortas (Figure, C). Moreover, the association between the elastic lamellae and tenascin-X was no longer seen in AAA (not shown).
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To study a possible association of AAA with tenascin-X serum levels, we collected sera from 87 individuals diagnosed with AAA and 86 age- and sex-matched control individuals and measured the serum levels of the 140-kDa fragment of tenascin-X. Table 1 shows the characteristics of patients with AAA and control individuals. The concentration of tenascin-X fitted a normal distribution for both groups, and no AAA patients were found with haploinsufficiency or a complete deficiency of tenascin-X. The median tenascin-X concentration in the patient group was 422 ng/mL (range, 251 to 602 ng/mL). The median tenascin-X concentration in the control group was significantly lower (378 ng/mL; range, 269 to 657 ng/mL; P<0.02). Of the 87 patients, 17 (20%) had a tenascin-X concentration above the 90th percentile of the controls, compared with 9 of the control subjects (crude OR, 2.4; 95% CI, 1.0 to 5.8).
To examine a possible dose–response relation, we stratified the tenascin-X concentrations into quartiles and calculated the ORs for the 3 highest levels compared with the lowest (Table 2). The OR increased significantly with tenascin-X concentration (P for trend, <0.005). Adjustment for known risk factors of AAA (smoking, systolic blood pressure, antihypertensive medication, age, and sex) slightly increased the ORs (Table 2). As shown in Table 1, AAA patients and controls differ with respect to a number of other characteristics, such as myocardial infarction, peripheral vascular disease, and use of cholesterol-lowering and nonsteroidal antiinflammatory drugs. Although these variables are not established risk factors for AAA, we performed an adjustment for each of these potential confounders separately. This did not affect the ORs in the quartiles of serum tenascin-X concentration. After adjustment for all of these variables together, the effect of tenascin-X remained virtually unchanged (OR, top versus bottom quartile, 3.9; 95% CI, 1.4 to 10.9).
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To further clarify whether tenascin-X serum levels are associated with peripheral vascular disease, cerebrovascular disease, or coronary artery disease, we calculated the ORs for the different quartiles of tenascin-X serum concentration and adjusted for age, sex, smoking, systolic blood pressure, use of antihypertensive medication, and AAA. No association was found between tenascin-X serum levels and cerebrovascular disease or coronary artery disease (data not shown). There were only 22 patients with peripheral vascular disease. However, our data are suggestive of an association between the risk of peripheral vascular disease and the concentration of serum tenascin-X (OR, top versus bottom quartile, 4.0; 95% CI, 0.88 to 20; P for trend, 0.047; Table 3). If the increased tenascin-X serum levels in AAA were due to increased proteolysis or increased synthesis of tenascin-X in the aneurysmal aortic wall, one would expect that tenascin-X serum levels would normalize after surgical repair of the aneurysm. Therefore, we determined the effect of surgery on tenascin-X serum levels in AAA patients by performing a subgroup analysis. Fifty-three patients with AAA received surgical treatment; of these patients, 40 underwent elective surgery, 7 were symptomatic, and 6 had a ruptured aneurysm. There was no significant difference in tenascin-X concentration in patients who underwent surgery (median, 432 ng/mL; range, 267 to 585 ng/mL) compared with those whose aneurysm was not repaired (median, 419 ng/mL; range, 251 to 602 ng/mL). The ORs in patients who did not have surgery and the ORs in patients who underwent surgery for their AAA are shown in Table 4. In both subgroups, an increased risk for AAA was found with increasing tenascin-X concentrations. No differences in tenascin-X serum levels were observed between symptomatic and asymptomatic patients and patients with a ruptured aneurysm.
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Discussion |
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Tenascin-X is expressed throughout the entire vascular wall, but its expression is particularly high near the elastic lamellae in the media. Previous studies have indicated that tenascin-X is highly expressed in fetal smooth muscle,15,21 possibly explaining the prominent expression of tenascin-X at the elastic lamellae. In AAA, the presence of tenascin-X in the aortic wall was strongly reduced, which could result in alterations of collagen and elastic fibers. Interestingly, a genetically determined absence of tenascin-X results in reduced collagen density and pronounced alterations in the elastic fibers of the skin.18 However, it is unlikely that a tenascin-X deficiency results in a generalized elastinopathy, because echocardiographic examination of tenascin-X–deficient patients did not show abnormalities in vessel wall compliance or the diameter of the aortic root and ascending aorta.22
A dose–response relation exists between tenascin-X levels in serum and the risk for AAA, and high tenascin-X levels remained a risk factor after adjustment for well-known risk factors, like smoking, age, and high blood pressure. We found an OR of 5.2 (95% CI, 2.0 to 13.8) for tenascin-X serum concentrations in the fourth quartile. In addition, serum tenascin-X concentration is associated with AAA independently of other potential risk factors, such as diseases and medications associated with AAA.
No association was found between tenascin-X serum levels and the risk of cerebrovascular or coronary artery disease, indicating that tenascin-X serum levels are an independent risk factor for AAA. Interestingly, this study indicated the possibility of an association between serum tenascin-X concentrations and peripheral vascular disease, but the association only just achieved statistical significance. However, the prevalence of peripheral vascular disease was significantly higher in patients with AAA compared with controls (P<0.001, by 
2 test). Although some studies support the hypothesis that the pathogenesis of peripheral vascular disease and AAA is distinct,23,24 our study does not rule out the possibility that tenascin-X might be involved in peripheral vascular disease.
No effect of AAA surgery on circulating tenascin-X levels was found, rendering it unlikely that increased tenascin-X serum levels reflect the extent of local vessel wall damage or locally increased tenascin-X synthesis. The latter is consistent with the observations in an experimental model for AAA, in which it was shown that tenascin-X mRNA expression is downregulated in the aorta during aneurysm formation.25 High tenascin-X levels could be a consequence of systemically increased turnover of tenascin-X; ie, it is possible that the alterations in tenascin-X expression in the aneurysmal aortic wall are also present in nonaneurysmal tissue of AAA patients, as has been described for elastin and collagen.26 Previous studies have shown that a genetically determined absence of tenascin-X is associated with altered properties of elastic fibers and collagen fibrils.16,18,27
The consequences of variations in the normal range of tenascin-X expression are unknown, but they could very well contribute to altered connective tissue properties. Speculatively, the increased tenascin-X serum levels in AAA patients could reflect turnover and leakage of tenascin-X from the vasculature, as a manifestation of a more general vascular disease in AAA patients. It is generally believed that AAA is a systemic disease, affecting the entire vasculature and not only the local aneurysmal wall. For example, it has been demonstrated that the mean diameter of peripheral arteries in patients with AAA is increased.28 Furthermore, the elastin-collagen ratio is reduced throughout the arterial vasculature.26 Recently, it has been shown that the expression of matrix metalloproteinase-2 is elevated in the vasculature remote from the aneurysm,8 providing further evidence for the systemic nature of AAA. Therefore, the elevated serum levels of tenascin-X are likely due to a systemic increased expression or breakdown of tenascin-X throughout the vasculature in patients with AAA. Loss of tenascin-X from the vessel wall could affect collagen fibril and elastic fiber properties, thereby causing weakness of the aortic wall. Tenascin-X has been shown to modulate collagen fibrillogenesis,29,30 as well as the organization of elastic fibers,18 which are both important components of the vascular wall.
Our study has several limitations that should be taken into account. First, the sample size of our study is relatively small. This is especially true for the tissue studies and the subgroup analyses concerning surgery and peripheral vascular disease. Furthermore, although we did adjust for several possible confounders, this does not exclude confounding by other unknown factors. Finally, we speculate that the decreased expression of tenascin-X in the aneurysmal wall might affect the organization of collagen fibrils and elastic fibers. However, because our study is a case-control study, no conclusions on causality can be drawn.
In conclusion, we found that tenascin-X expression is markedly decreased in AAA tissue and that AAA is associated with high serum concentrations of tenascin-X. Clearly, a large prospective study is needed to confirm the observed association between serum tenascin-X concentration and AAA and to determine the direction of the effect.
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Acknowledgments |
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This work was supported by grants to M. den Heijer from the Netherlands Organization for Scientific Research (VENI-grant) and to J. Schalkwijk from the Radboud University Medical Centre (vrije beleidsruimte). We thank W. van Iersel for excellent assistance in collecting data. We are indebted to S. Frouws, radiologist, for his valuable help. We thank J. Bristow for his kind gift of rabbit polyclonal anti–tenascin-X antibody.
Disclosures
None.
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Footnotes |
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*Drs den Heijer and Schalkwijk contributed equally to this work.
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