(Circulation. 1995;92:2969-2974.)
© 1995 American Heart Association, Inc.
Articles |
Plasma Endothelin Correlates With Antiendothelial Antibodies in Patients With Mixed Connective Tissue Disease
From the Research Center (J.G.F.), Maisonneuve-Rosemont Hospital, Department of Medicine, University of Montréal, Montréal, Quebec, Canada; and Third Department of Medicine (E.B., S.S., E.G., I.C., G.S.), Debrecen University Medical School, Debrecen, Hungary.
Correspondence to János G. Filep, MD, Research Center, Maisonneuve-Rosemont Hospital, University of Montréal, 5415 Boulevard de l'Assomption, Montréal, Quebec, Canada H1T 2M4.
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Abstract |
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Background Elevated circulating levels of the vasoactive peptide endothelin-1 have been reported in various cardiovascular disorders. Because these conditions are frequently associated with endothelial dysfunction and damage and the vasoconstrictor effect of endothelin-1 is believed to be produced at the local vascular level, it is uncertain whether circulating endothelin-1 is a causal factor in enhanced vascular tone or instead a marker of endothelial injury.
Methods and Results We tested whether elevated immunoreactive endothelin-1 could be detected by radioimmunoassay in plasma and whether endothelin-1 levels correlated with antiendothelial autoantibodies in patients with mixed connective tissue disease. Venous blood samples were collected from 21 patients in the morning after an overnight fast and before medication. The plasma immunoreactive endothelin-1 level was 2.7±0.5 pg/mL (range, 1.1 to 5.2 pg/ml; n=9) and 7.3±1.5 pg/mL (range, 2.8 to 20.7 pg/mL; n=12) in patients who had no antiendothelial antibodies and in patients with antiendothelial antibodies, respectively. These latter values were significantly (P<.001) increased compared with 10 age-matched healthy volunteers (2.0±0.3 pg/mL; range, 0.5 to 3.0 pg/mL). Plasma endothelin-1 level strongly correlated with antiendothelial antibodies (rs=.836, n=21, P<.001), whereas there was no correlation between age, systolic and diastolic blood pressures, antinuclear antibodies, and duration of the disease and endothelin-1 values. The incidence of Raynaud's phenomenon and angina did not differ significantly in patients with low and high endothelin-1 levels.
Conclusions This study showed that mixed connective tissue disease is associated with elevated plasma immunoreactive endothelin-1 and that endothelin-1 levels significantly correlate with antiendothelial autoantibodies. These findings suggest that increases in plasma endothelin-1 concentration may be secondary to vascular injury and do not necessarily represent enhanced susceptibility to vasoconstriction.
Key Words: endothelin • antibodies • endothelium
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Endothelin-1 is a member of a family of potent vasoactive peptides1 with wide range of biological activities.2 3 Numerous pharmacological studies demonstrating its potent long-lasting vasoconstrictor and pressor activities2 3 have led to the concept that endothelin-1 plays an important pathophysiological role in local and systemic vasoconstriction. Elevated circulating levels of endothelin-1 have been detected in various cardiovascular disorders, including ischemic heart disease,4 5 essential hypertension,6 pulmonary hypertension,7 8 and cardiogenic9 and endotoxic shock.10 These pathologies are frequently associated with endothelial dysfunction and/or damage.11 12 13 14 Because endothelial cells respond to injury by altering the expression of various genes, including the endothelin-1 gene, with subsequent alterations in mediator generation,15 it is still uncertain whether endothelin-1 is a causal factor in vasoconstriction or instead a marker of endothelial injury. Moreover, markedly high endothelin-1 levels have been reported in some rheumatic diseases, such as systemic lupus erythematosus16 17 and primary and secondary Raynaud's phenomenon,17 18 19 in which autoimmune mechanisms are believed to be responsible for the vascular damage. The overlapping form of rheumatic diseases, called mixed connective tissue disease, is characterized by high levels of circulating autoantibodies and by a diffuse proliferative intimal and/or medial vascular lesion, resulting in narrowing of the lumen of small vessels as well as of medium-size arteries of many organs.20 In the present study, we investigated whether the presence of antiendothelial autoantibodies is associated with elevated plasma levels of endothelin-1 in patients with mixed connective tissue disease.
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Methods |
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Patient Population
We studied 21 white patients with mixed connective tissue disease who visited our ambulatory clinic for regular follow-up examinations between September 1993 and November 1993. During their treatment by us, all patients fulfilled at least once the preliminary criteria for mixed connective tissue disease introduced by the 1986 International Symposium on Mixed Connective Tissue Disease and Antinuclear Antibodies20 based on the original description of Sharp et al.21 Major criteria included myositis, pulmonary involvement, Raynaud's phenomenon, swollen hands or sclerodactyly, and antibodies against a nuclear ribonucleoprotein (anti-RNP). None of the patients fulfilled the American College of Rheumatology criteria for systemic lupus erythematosus22 (Table 1
), Sjögren's
syndrome (absence of
keratoconjunctivitis sicca and xerostomia), or systemic
sclerosis23 (absence of proximal scleroderma, digital
ulceration or scars, loss of substance of the distal finger pad, and
bibasilar pulmonary fibrosis in patients with sclerodactyly).
In addition, the patients' sera did not contain autoantibodies against
DNA topoisomerase I (scl 70) and centromere, which are
characteristic of diffuse scleroderma and the limited form of
scleroderma (CREST syndrome), respectively.24 None of the
patients had Wegener's granulomatosis or polyarteritis nodosa. The
patients were divided into those who had no
antiendothelial antibodies in the plasma (group 1)
and those who had antiendothelial antibodies (group
2). Patient characteristics are given in Table 1. Seven
patients in
group 2 who showed signs of exacerbation of arthritis and myositis with
concomitant increases in erythrocyte sedimentation rate and serum
creatine kinase level were considered to have a more active stage of
the disease (Table 2). Duration of disease (in years)
was measured from onset of symptoms. Disease activity
parameters were stable at the time of the study. Sixteen
patients were undergoing low-dose steroid therapy and 14 were
taking calcium channel blockers for symptomatic treatment
of Raynaud's phenomenon. Patients who were taking more than 5 mg/d
prednisolone were excluded from the study. Ten healthy female
volunteers (mean age, 36 years; range, 28 to 48 years) constituted the
control group. Blood samples were collected in the morning after an
overnight fast and before medication. Blood was drawn from the
antecubital vein into prechilled tubes containing EDTA and was
immediately centrifuged at 1600g for 20 min, and
plasma was frozen and stored at -80°C until assay. To assess
vascular lesions, a biopsy from the affected skin areas was also
performed. Conventional light microscopic analysis of the
biopsy specimens, fixed in formalin and stained with hematoxylin and
eosin, was done by an observer unaware of the patients' clinical
condition. Informed consent was obtained from all patients and
volunteers before participation in the study, and the protocol was
approved by the institutional committee on human subjects and
research.
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Measurement of Antinuclear and
Antiendothelial Autoantibodies
Plasma concentrations of antibodies
against a nuclear
ribonucleoprotein (anti-RNP), against a protein complexed to
Y1Y5 RNA (anti-SSA), and against a
phosphoprotein complexed with RNA pol III transcripts (anti-SSB) were
determined by an indirect ELISA method with commercial immunowell kits
(General Biometrics Inc) in accordance with the manufacturer's
protocol.
Plasma levels of antiendothelial cell autoantibodies were determined by a cellular ELISA with cultured human umbilical vein endothelial cells according to the method of Frampton et al.25 In brief, endothelial cells harvested from human umbilical cord veins with 0.2% collagenase were grown in Dulbecco's complete medium26 supplemented with 30 µg/mL endothelial cell growth factor (Sigma Chemical Co) and 10 units/mL heparin (Leo Laboratories). Second-passage endothelial cells were seeded at 2x104 in 100 µL on sterile 96-well microtiter plates (Costar) precoated with 100 µL of 1% gelatin. The identity of endothelial cells was verified by morphology and by immunofluorescence staining using a rabbit anti-human factor VIII antigen antibody (Behring). After 48 hours of culture, the plates were washed three times with phosphate-buffered saline (0.15 mol/L, pH 7.4), fixed with 0.2% glutaraldehyde for 15 minutes at 22°C, washed twice with PBS containing 0.2% BSA, and then incubated with PBS containing 1% BSA and 0.1 mol/L glycine for 1 hour at 22°C to block nonspecific binding of immunoglobulins. After three washes, 100 µL of test or reference samples diluted 1:20 was added to each well in triplicate and incubated for 2 hours at 22°C. After three washes, 100 µL of peroxidase-conjugated goat anti-human IgG F(ab')2 antibody and peroxidase-conjugated goat anti-human IgM antibody (Cappel Laboratories) diluted 1:500 in PBS containing 2% BSA was added to each well for an additional 2 hours at 22°C. After three washes, 100 µL of 4 mmol/L O-phenylene diamine dihydrochloride (Sigma Chemical Co) and 1.3 mmol/L hydrogen peroxide in 0.1 mol/L citrate buffer, pH 5.0, was added to each well for 20 minutes at 22°C. The reaction was terminated by the addition of 100 µL of 2 mol/L sulfuric acid, and the optical density was measured at 492 nm in a microplate reader. Two positive and two negative control sera were included on each plate. Samples were considered positive for antiendothelial antibodies if test values were greater than the mean+2 SD value of 23 healthy subjects. The intra-assay and interassay coefficients of variation were 5% and 9%, respectively.
Measurement of Plasma Endothelin-1
Plasma endothelin was
extracted with the use of octadecyl silica
cartridges (Sep Pak, Waters) and immunoreactive endothelin-1
concentrations were measured with a double-antibody
radioimmunoassay kit (Peninsula Laboratories) as described
previously.27 The extraction procedure yielded a recovery
of 62±3% as assayed by calculating the recovery of exogenous
endothelin-1, which had been added to the plasma. The values reported
in the present study should be considered immunoreactive
endothelin-1 as the antiserum exhibited a cross-reactivity of 17%
for human big endothelin-1 and 7% for endothelin-2 and endothelin-3
but no cross-reactivity with unrelated peptides
(angiotensin I and II, vasopressin, and atrial and brain
natriuretic peptides). The detection limit of the assay was
0.1 pg per tube. The intra-assay coefficient of variation was 4%
at the midpoint (2.2 pg per tube) of the standard curve. Dilution
curves of known endothelin-1 concentrations added to plasma were
parallel to the standard curve, which suggested an absence of
interfering substances in the plasma samples. All endothelin-1 values
were corrected for recovery and expressed as picograms per milliliter
plasma.
Statistical Analysis
Group values are presented as
mean±SEM. The occurrence
of clinical features in patients with and without
antiendothelial antibodies was compared with the
use of Fisher's exact test. Plasma endothelin-1 levels in healthy
volunteers and in the two groups of patients were compared by
one-way ANOVA using ranks (Kruskal-Wallis test) followed by Dunn's
multiple-contrast hypothesis test to identify differences between
groups. Comparison of systolic and diastolic blood
pressures and anti-RNP antibody in the two groups of patients was made
with two-tailed Mann-Whitney U test. To identify
relevant relations, regression analysis of age, blood pressure,
and antinuclear or antiendothelial autoantibodies
with plasma endothelin-1 was performed by calculating Spearman's rank
correlation coefficients (rs). Where
appropriate, polynomial regression was also performed. A value of
P<.05 was considered significant for all tests.
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Results |
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Healthy Subjects
The control group consisted of 10 women. Resting systolic and diastolic blood pressures were 123±3 and 79±3 mm Hg, respectively. In healthy subjects, the plasma endothelin-1 level was 2.0±0.3 pg/mL (range, 0.5 to 3.0 pg/mL) (Fig 1
).
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Patients With Mixed Connective Tissue Disease
The
characteristics of patients in each group are given in Table 1
.
No significant differences could be detected in these
parameters with the exception that group 1 contained one
male patient. The Kruskal-Wallis test indicated that variation in age
and systolic and diastolic blood pressures among
medians of control subjects and patients in groups 1 and 2 was not
significantly greater (P>.06) than expected by chance.
Increased circulating levels of immunoreactive endothelin-1 were
present in most patients with mixed connective tissue disease. The
plasma endothelin-1 level was on average 41% higher in patients who
had no antiendothelial antibodies than in control
subjects, whereas the mean value of plasma endothelin-1 was more than
threefold the control level in patients with
antiendothelial autoantibodies (Fig 1). The range
of values demonstrated minimal overlap between these two populations
(Fig 1). There was no correlation between age, systolic or
diastolic blood pressures, and endothelin-1 values for
either healthy subjects (Spearman's rank correlation coefficients were
-.201, .346, and .398, respectively; n=10, P>.2 for
each
correlation) or patients with mixed connective tissue disease
(Spearman's rank correlation coefficients were -.103, .238, and
.230,
respectively; n=21, P>.2 for each correlation).
Furthermore, plasma endothelin-1 levels correlated with neither the
duration of the disease (rs=.1734, n=21,
P>.45) or the duration from the first observation of
Raynaud's phenomenon (rs=.3041, n=14,
P>.29). The Spearman correlation analysis revealed
a highly significant, positive correlation of endothelin-1 with
antiendothelial autoantibodies in patients with
mixed connective tissue disease (rs=.831, 95%
confidence limit of .614 to .931, n=21, P<.001). Although
significant by either linear or polynomial regression analysis,
endothelin-1 levels were best described by nonlinear polynomial
regression (Fig 2). The index of determination
(r2) indicated that at least 61% of the
variability of plasma endothelin-1 level was related to the variability
of plasma antiendothelial autoantibodies. No
significant correlations could be detected between plasma levels of
endothelin-1 and anti-RNP antibodies
(rs=.328, n=21, P>.14) and
between
endothelin-1 concentrations and occurrence of anti-SSA or anti-SSB
autoantibodies in patients with or without
antiendothelial autoantibodies.
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Patients in group 2 were divided into
two subgroups, with group 2b
consisting of patients considered to have a more active stage of the
disease (Table 2). There were no significant differences
in age, duration of the disease, systolic and
diastolic blood pressures, and plasma levels of anti-RNP
autoantibodies between these two subgroups of patients. On the other
hand, plasma concentrations of both antiendothelial
antibodies and endothelin-1 were significantly higher in patients with
a more active stage of the disease (Table 2). The prevalence of
Raynaud's phenomenon and vascular lesions did not differ significantly
between the two subgroups (Table 2). Histological
evaluation of skin biopsy specimens showed the presence of vascular
damage characterized by intimal proliferation and medial
hypertrophy in venules and arterioles without fibrosis,
occasional extravasation of erythrocytes, and infiltration of
perivascular area and, less often, the vessel wall by mononuclear
cells. Leukocytoclastic infiltration was observed only in three
patients of group 2b (Table 2).
To assess further the possible association of plasma endothelin-1 with Raynaud's phenomenon, plasma endothelin-1 concentrations were compared in group 2 patients with or without Raynaud's phenomenon. Plasma endothelin-1 levels of patients with Raynaud's phenomenon (8.8±2.5 pg/mL; range, 3.7 to 20.7 pg/mL; n=6) did not differ significantly (P=.39, Mann-Whitney U test) from those detected in patients who do not have Raynaud's phenomenon (5.8±1.4 pg/mL; range, 2.8 to 11.4 pg/mL; n=6).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present study, patients with mixed connective tissue disease with antiendothelial antibodies were found to have a mean peripheral venous plasma endothelin-1 concentration three times higher than that of age- and sex-matched healthy subjects. The normal values in our study are consistent with previously published values.4 5 6 7 8 9 It should, however, be noted that the antibody used in our assay cross-reacts with the precursor of endothelin-1, big endothelin-1, endothelin-2, and endothelin-3. The contribution of these two latter endothelins to the immunoreactivity is negligible as endothelin-2 has not been found to circulate in humans2 3 28 and the plasma level of endothelin-3 is less than one half of that of endothelin-1.28 The molar ratio of big endothelin-1 to endothelin-1 is
1 in the plasma of healthy
subjects.4 29 As big endothelin-1 is normally
converted to
the biologically active peptide endothelin-1, the assay would estimate
both potential and actual endothelin-1 bioactivity. We cannot exclude
the possibility that conversion of big endothelin-1 to endothelin-1 is
impaired in mixed connective tissue disease. Consequently, the high
plasma levels detected might reflect an increase mainly in big
endothelin-1, rather than endothelin-1. However, there would have to be
a very high increase in big endothelin-1 to account for a threefold
increase in endothelin-1 immunoreactivity because the antibody used had
only 17% cross-reactivity with big endothelin-1. Therefore, the
raised level of immunoreactive endothelin-1 in our patients could be
considered as a reflection of the biologically active peptide. The
small amount of endothelin-1 in the plasma did not allow testing for
bioactivity. Our data demonstrate for the first time a strong positive correlation of plasma endothelin-1 concentrations with levels of antiendothelial antibodies in patients with immune-mediated vascular injury. The importance of this relation was identified by the Spearman nonparametric correlation analysis and polynomial regression analysis. In the latter analysis, the index of determination (r2) indicated that at least 61% of the variability in plasma endothelin-1 was related to the variability of plasma antiendothelial antibodies. The naturally occurring human antiendothelial antibodies are of the IgM class30 and in lesser extent of the IgG class.31 Because both IgG and IgM antibodies could be detected frequently in patients with systemic vasculitis,25 in the present study we measured the combined level of IgG plus IgM autoantibodies in each sample. Endothelial cells express immunogenic molecules of the class I (HLA-A, -B, and -C); class II (HLA-DR) major histocompatibility complex; the adhesion molecules ICAM-1, VCAM-1, and PECAM; and a 60/62-kD doublet of unknown nature.31 No information is available at present whether the autoantibodies are directed against one or more of these molecules. Antiendothelial antibodies of the IgM class can be highly destructive and have been implicated in the rejection of porcine xenografts30 and in the development of transplant-associated coronary artery disease.31 The possibility that antiendothelial autoantibodies mediate vascular injury in mixed connective tissue disease is suggested, although far from confirmed, by the demonstration that these autoantibodies induce lysis of endothelial cells in vitro and by the observation that patients with an apparently more active stage of the disease had higher plasma levels of antiendothelial autoantibodies. In addition, leukocytoclasis, which is believed to be indicative for a more active stage of vasculitis, was detected in skin biopsies from only three of these patients. An alternative possibility might be that antiendothelial cell autoantibodies are produced against already damaged cells, and therefore they are markers rather than mediators of vascular damage. Consequently, the close correlation between plasma levels of antiendothelial antibodies and endothelin-1 would not reflect a casual relation but would indicate the usefulness of either antiendothelial autoantibodies or endothelin-1 as markers of vascular damage regardless of the damage-inducing mechanism(s). Although chronic endothelial stimulation (eg, mechanical forces or cytokines) and/or endothelial injury has been reported to enhance transcription of the endothelin-1 gene in endothelial cells,15 little is known about the underlying mechanisms.
If one assumes that immunoreactive endothelin-1 in our patients reflects biologically active endothelin-1, it would be important to know whether endothelin-1 actually contributes to the pathophysiology of the disease. A vasoconstrictor role for endothelin-1 remains uncertain because even the highest plasma levels of endothelin-1 we found in vasculitis patients were still below the threshold (10 pmol/L) for inducing contraction of isolated vascular rings1 or a systemic pressor response in humans.32 Furthermore, in view of the similarities in systemic and diastolic blood pressure values and in the incidence of Raynaud's phenomenon and angina in patients with low (group 1) and high (group 2) endothelin-1 levels coupled with the findings that plasma endothelin-1 levels do not differ significantly in patients of group 2 with and without Raynaud's phenomenon, it appears that elevations in plasma endothelin-1 do not necessarily reflect enhanced susceptibility to vasoconstriction, as suggested previously.18 Instead, elevated plasma endothelin-1 in our patients appears to be a marker of endothelial damage rather than a mediator of vasoconstriction. The findings that plasma endothelin-1 correlated with plasma von Willebrand factor, a known marker of endothelial damage,33 in patients with primary Raynaud's phenomenon19 lend further support to this notion. On the other hand, because release of endothelin-1 by endothelial cells is polarized toward the basolateral side,34 plasma levels of endothelin-1 may not correctly represent local production rate, and local concentrations of endothelin-1 might be much higher than those detected in the plasma. It is possible that by virtue of its mitogenic2 35 and vascular permeability–enhancing36 effects, endothelin-1 may contribute to proliferation of vascular smooth muscle cells and deposition of IgG and IgM within the vascular wall.20
In conclusion, we have shown that elevated plasma levels of immunoreactive endothelin-1 specifically correlate with antiendothelial antibodies in patients with mixed connective tissue disease. These findings suggest that increases in plasma endothelin-1 concentration may be secondary to vascular injury and do not necessarily represent enhanced susceptibility to vasoconstriction. Direct assessment of the functional importance of endothelin-1 in this disorder must await the use of orally active endothelin-1 receptor antagonists or inhibitors of its production.
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Acknowledgments |
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This work was supported by the Medical Research Council of Canada, the Foundation of the Maisonneuve-Rosemont Hospital, and the Hungarian National Foundation for Scientific Research. Dr Filep is a Senior Scholar of the Fonds de la Recherche en Santé du Québec (FRSQ).
Received November 29, 1994; revision received May 31, 1995; accepted June 23, 1995.
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