© 1997 American Heart Association, Inc.
Articles |
Homocysteine as a Risk Factor for Vascular Disease
Enhanced Collagen Production and Accumulation by Smooth Muscle Cells
From the Department of Cell Biology, Research Institute, Cleveland Clinic Foundation, Ohio. Drs Majors and Pezacka are now affiliated with the Department of Human Genetics, Allegheny University of the Health Sciences, Pittsburgh, Pa.
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Abstract |
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Abstract An increased plasma homocysteine level is an independent risk factor for vascular disease. However, the pathological mechanisms by which homocysteine promotes atherosclerosis are not yet clearly defined. Arterial smooth muscle cells cultured in the presence of homocysteine grew to a higher density and produced and accumulated collagen at levels significantly above control values. Homocysteine concentrations as low as 50 µmol/L significantly increased both cell density and collagen production. Cell density increased by as much as 43% in homocysteine-treated cultures. Homocysteine increased collagen production in a dose-dependent manner. Smooth muscle cells treated with homocysteine at concentrations observed in patients with hyperhomocysteinemia had collagen synthesis rates as high as 214% of control values. Likewise, collagen accumulation in the cell layer was nearly doubled in homocysteine-treated cultures. Addition of aquacobalamin to homocysteine-treated cultures controlled the increase in smooth muscle cell proliferation and collagen production. These results indicate a cellular mechanism for the atherogenicity of homocysteine and provide insight into a potential preventive treatment.
Key Words: collagen • atherosclerosis • homocysteine • smooth muscle cell • extracellular matrix
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Introduction |
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Homocysteine is a sulfhydryl-containing amino acid produced as an intermediate of the methionine conservation cycle and the one-carbon metabolic and transsulfuration pathways (Fig 1
). Normal plasma total Hcy
concentrations range from 5 to 15 µmol/L, and patients
with plasma Hcy concentrations above 15 µmol/L are
considered to have hyperhomocysteinemia.1 Increased levels
of Hcy in human plasma can be caused by either inherited or acquired
conditions. Acquired conditions may be secondary to chronic disorders,
prolonged drug therapy, or an abnormal nutritional state.2
A common polymorphism in the tetrahyrofolate reductase gene
resulting in mild hyperhomocysteinemia is believed to be a risk factor
for cardiovascular disease.3 4
Life-threatening hyperhomocysteinemia, resulting in vascular disease at
a young age, is associated with enzymatic defects at various points of
Hcy metabolism5 6 7 8 (Fig 1). Plasma Hcy levels
can be as high as 500 µmol/L in patients who exhibit
severe atherosclerosis and have either acquired or
inherited functional cobalamin deficiency or cystathionine ß-synthase
deficiency that does not respond to PLP treatment.5 6 7 8 9
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The methylation of Hcy to regenerate methionine is catalyzed by the
Cbl-dependent enzyme methionine synthase (Fig 1
). Impairment of this
remethylation pathway can result in hyperhomocysteinemia. A correlation
between low serum levels of Cbl and hyperhomocysteinemia has been
observed in a number of severely Cbl-deficient
patients.10 11 Although the serum vitamin B12
(CN-Cbl) assay is an extremely sensitive test for Cbl deficiency, it
lacks specificity. The true intracellular deficiency of biologically
active Cbl, as evidenced by increased plasma Hcy, does not always
correlate with marginally low levels of serum CN-Cbl.12 13
CN-Cbl is not the biologically active form of Cbl; CN-Cbl must be
converted to aqCbl to become a precursor of the Cbl II that is bound by
apo-methionine synthase (Fig 1). Patients with genetically impaired
remethylation of Hcy caused by Cbl C, D, and E mutations involving the
intracellular metabolism of Cbl can have normal plasma Cbl
levels but still be hyperhomocysteinemic.5 6 7 8 Such
patients, when treated with hydroxocobalamin, which is converted to
aqCbl at physiological pH, improve
clinically.14 15 16 Even in normal rats, hydroxocobalamin
infusion enhances liver methionine synthase activity to 132% of
control values and reduces serum Hcy concentrations to 74% of control
levels despite normal plasma levels of CN-Cbl.17
Recently, a strong correlation has been established between elevated levels of plasma Hcy and vascular disease, regardless of the underlying metabolic cause.18 19 Elevated plasma Hcy levels have been found in patients with coronary artery disease, cerebrovascular disease, or peripheral vascular disease.20 21 22 23 24 25 However, the mechanisms by which Hcy promotes atherosclerotic plaque formation are not clearly defined. SMC migration and proliferation and collagen deposition are hallmarks of atherosclerosis. Tsai et al26 27 have demonstrated that short-term exposure of SMCs to Hcy enhances cellular proliferation. These experiments were performed, however, in culture medium that does not contain Cbl. Because only 0.4% serum was used in these experiments, the contribution of Cbl from the serum would be small, only 1 to 2 pmol/L, which may be insufficient for rapidly proliferating cells. It has not been shown whether or not the addition of either CN-Cbl or aqCbl may minimize the mitogenic effect of Hcy on SMCs. The effects of Hcy on SMC collagen synthesis are not known. To further elucidate the pathological mechanisms involved in Hcy-induced atherosclerosis, we examined the effect of Hcy on cell proliferation, collagen synthesis, and collagen accumulation in cultured arterial SMCs.
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Methods |
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Materials
All chemicals were purchased from Sigma Chemical Company unless stated otherwise.
Cell Culture
Rabbit aortic SMCs were obtained from explants of the medial
layer from the thoracic aorta of a young male rabbit and cultured as
previously described.28 Briefly, cells were grown in
DME/F12 (1:1) medium (Irvine Scientific) that contained 0.12%
NaHCO3 and 10% FBS (Bio-Whitaker). Amino acid
supplementation (MEM nonessential amino acids supplement, Irvine
Scientific) resulted in a final concentration of 0.25
mmol/L L-proline. The total cyst(e)ine concentration
was within the physiological range (300
µmol/L), and the concentration of CN-Cbl was 500
nmol/L. Cultures were maintained at 37°C in 95% air and 5%
CO2. Unless otherwise stated, six-well tissue-culture
plates (Costar) were used in experiments. SMC cultures from passages 5
to 8 were used. Cultures were confluent within the first week and were
postconfluent for all experiments. SMC cultures were fed 3 to 4 times
per week with medium containing freshly made Hcy.
Hcy Preparation
L-Hcy was prepared from L-Hcy
thiolactone as described29 Briefly, Hcy thiolactone was
dissolved in water, hydrolyzed with KOH for 12 minutes at 45°C,
neutralized with HCl (Fisher Scientific), and cooled to 0°C with
constant nitrogen purging. Freshly prepared Hcy was used in all
experiments.
Collagen and Total Protein Synthesis
Cultures were labeled as previously described28 for
5 hours with 10 µCi/mL L-[2,3-3H]proline
(New England Nuclear) and 2.5x10-4
mol/L sodium ascorbate. The collagen digestion assay
30 31 32 was used to quantify collagen and noncollagenous
protein synthesis. Briefly, culture medium and cell layers were
combined and precipitated on ice with 10% TCA containing 0.5% tannic
acid. Precipitated material was washed extensively at 4°C with 5%
TCA containing 0.25% tannic acid and 1 mmol/L
L-proline. The labeled protein was resuspended in 0.2N NaOH
and an aliquot was subjected to the collagen digestion assay as
described30 31 32 using collagenase form III from
Clostridium histolyticum (Advanced Biofactures). After
overnight digestion at 37°C, TCA and tannic acid were added to final
concentrations of 5% and 0.25%, respectively. The nonprecipitable
material was subjected to scintillation counting to determine the
amount of radioactivity present. The TCA-precipitable material was
resuspended in 0.2N NaOH and an aliquot was denatured with Soluene
(Packard Instrument Co), neutralized with HCl, and subjected to
scintillation counting.
DNA Determination
Cultures were trypsinized, resuspended in phosphate buffer, and
sonicated as described.32 DNA concentration was determined
fluorimetrically by the method of Labarca and Paigen.33
Hydroxyproline Analysis
SMCs were plated sparsely (2.7x102/mm2)
into 100-mm petri dishes (Costar) and grown for 3 weeks in DME/F12
medium containing 10% FBS and 2.5x10-4
mol/L sodium ascorbate with or without 300 µmol/L
Hcy. Conditioned medium was aspirated and cell layers were rinsed twice
with PBS. A solution of 5% TCA/0.25% tannic acid was added and the
petri dishes were placed in a -70°C freezer. Cell layers were later
scraped, centrifuged, and rinsed once in 5% TCA/0.25% tannic
acid. Precipitated protein was resuspended in 6N HCl and hydrolyzed at
120°C for 18 hours. Hydrolysates were filtered, evaporated, and
resuspended in deionized water.28 Hydroxyproline was
assayed colorimetrically by the method of Bergman and
Loxley.34 Hydroxyproline was not detectable in SMCs grown
in the absence of sodium ascorbate.
Data Analysis
Statistical analysis was performed with SPSS for Windows
(SPSS Inc). Statistical comparisons between groups were performed using
ANOVA for multiple comparisons, and when significant, this
analysis was followed by multiple two-tailed Student's
t tests. Differences were considered significant at a value
of P<.05. Pearson's correlation coefficients were
used.
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Results |
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The long-term effects of Hcy on SMCs were determined by growing rabbit aortic SMCs for 3 weeks with or without Hcy in the culture medium. The standard culture medium used in all experiments contained physiological concentrations of Cys and high levels of CN-Cbl. Cell densities increased significantly with increasing concentrations of added Hcy, as indicated by their DNA contents (Fig 2
). DNA content reached a maximum (143%
of control values) at an Hcy concentration of 300 µmol/L,
and this concentration was used in subsequent experiments. All results
have been normalized to the DNA content of the cultures to account for
differing cell numbers.
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Collagen synthesis by SMCs cultured for 3 weeks in the presence of
increasing concentrations of Hcy increased in a dose-dependent manner
(r2=.99, Fig 3). Adding only 50 µmol/L
Hcy to SMC cultures significantly increased collagen synthesis by 16%.
SMCs treated with 500 µmol/L Hcy synthesized 214% of the
amount of total collagen produced by control cultures.
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represents collagen synthesis per nanogram DNA and 
,
noncollagenous protein synthesis per nanogram DNA. *P<.01
relative to control SMCs with no added Hcy; **P<.005; and
***P<.001.
Hcy also increased SMC synthesis of noncollagenous proteins, but only
at concentrations of 200 µmol/L and higher (Fig 3).
However, Hcy increased noncollagenous protein synthesis by only 17%
compared with a 114% increase in collagen synthesis.
Collagen synthesis, expressed as a percentage of total protein
synthesis (relative collagen synthesis), also increased incrementally
with increasing concentrations of Hcy
(r2=.96, Fig 4), rising from 2.7% in control cultures
to 4.8% in cultures treated with 500 µmol/L Hcy.
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Collagen accumulation is the net result of collagen synthesis and
degradation. To determine whether the excess collagen produced by
Hcy-treated cells was accumulating, we assayed the hydroxyproline
contents of the cell layers as a measure of insoluble collagen
accumulation. Fig 5 shows that cell
layers of SMCs grown for only 3 weeks with 300 µmol/L Hcy
accumulated 1.9 times the amount of insoluble collagen per nanogram DNA
than cell layers from control SMCs.
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To determine whether the free thiol group may be important for
modulating SMC proliferation and collagen synthesis, we also tested the
effects of exogenously added Cys and AdoHcy. The standard culture
medium used in all experiments already contained 300
µmol/L Cys total. Further addition of Cys to a final
concentration of 600 µmol/L, which is twice the
physiological plasma level, increased SMC collagen
synthesis per nanogram DNA to a similar but lesser extent than Hcy (Fig 6). Cys also increased the DNA content of
SMC cultures, but only to 86% of the amount attained by Hcy treatment.
AdoHcy had no effect on either DNA content or collagen synthesis (Fig 6).
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We analyzed the effect of aqCbl on SMC proliferation and
collagen synthesis by SMCs cultured in the presence of Hcy. Adding
aqCbl to Hcy-treated cultures significantly reduced their DNA contents,
while the DNA contents of cultures treated with aqCbl alone were
similar to control values (Fig 7). The
addition of aqCbl to Hcy-treated cultures also reduced SMC collagen
synthesis per nanogram DNA to nearly half that produced by SMCs
cultured with Hcy alone (Fig 8). Total
protein synthesis induced by Hcy was also significantly reduced by the
addition of aqCbl (Fig 8). However, when SMCs were cultured with aqCbl
alone, neither collagen nor total protein synthesis was affected (Fig 8).
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Discussion |
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Numerous studies have indicated that even moderate hyperhomocysteinemia is an independent risk factor for vascular disease. Atherosclerosis is characterized by an extensive thickening of the arterial intima that is associated with both SMC proliferation and the excessive deposition of extracellular matrix protein by intimal SMCs.35 36 Collagen is the major component of these atherosclerotic plaques, representing up to 60% of the total protein present.37 We have shown the long-term effects of moderate to high pathophysiological concentrations of Hcy on SMCs by culturing SMCs for 3 weeks with or without Hcy in the culture medium.
Cell density increased with increasing concentrations of Hcy. Hcy concentrations as low as 50 µmol/L, which is only 3.3 times the upper range of Hcy concentrations in normal plasma, significantly increased the DNA content of SMC cultures. These results demonstrate that Hcy, at concentrations found in the plasma of hyperhomocysteinemic patients, can promote the growth of SMCs.
We have also found that the synthesis of collagen by SMCs cultured in the presence of Hcy increased dramatically in a dose-dependent manner. Hcy concentrations as low as 50 µmol/L significantly increased SMC collagen synthesis. SMCs treated with 500 µmol/L Hcy synthesized more than double the amount of collagen produced by control SMCs. Relative collagen synthesis also increased dramatically with increasing Hcy concentrations, indicating a preferential increase in collagen production. In contrast, noncollagenous protein synthesis was increased by only a maximum of 17% and only at Hcy concentrations of 200 µmol/L and higher. These observations show that the enhanced production of collagen was preferential and not simply the result of a general increase in protein synthesis or a higher specific activity of the radiolabeled proline in treated versus control cells.
The increase in SMC collagen synthesis by Hcy was accompanied by an excessive accumulation of insoluble collagen in the cell layer, demonstrating that the excess collagen produced was not simply degraded. This is consistent with the finding that hydroxyproline accumulates in the aortas of rats fed Hcy for 6 weeks.38 Such dramatic increases in collagen synthesis and accumulation over a relatively short period are also consistent with the accumulation of collagen in atherosclerotic plaques in children with premature atherosclerosis resulting from severe hyperhomocysteinemia.5 6 7 8 39
Previous studies have demonstrated that the free thiol group of Hcy is involved in mediating many of the effects of Hcy.27 40 41 42 In agreement with these findings, we showed that Cys but not AdoHcy enhanced SMC proliferation and collagen synthesis, suggesting that the sulfhydryl group of Hcy is likely to be mediating its effects. While providing useful information with respect to the mechanism by which Hcy upregulates SMC proliferation and collagen synthesis, the similar enhancement of these processes by Cys is unlikely to be physiologically relevant, because such high Cys concentrations are not normally observed in vivo. The total plasma cysteine concentration is only 200 to 350 µmol/L.43 44 Patients with defects in the transsulfuration pathway, with cystinuria, or cystinosis do not have elevated plasma levels of cysteine.6 45 46 Only patients requiring hemodialysis have been observed to have dramatically elevated plasma cysteine levels.47 48 However, other amino acids, including Hcy, are also elevated in such patients.47 Because cysteine is believed to be an important regulator of the distribution of Hcy between reduced and oxidized forms,2 it is important for in vitro experiments to use cysteine concentrations in the physiological range. Our findings show that in standard culture medium containing physiological concentrations of cysteine (300 µmol/L), Hcy enhances both SMC proliferation and collagen synthesis.
The addition of aqCbl inhibited the Hcy-induced enhancement of SMC
proliferation, collagen synthesis, and total protein synthesis. When
SMCs were cultured with aqCbl alone, neither cell density, collagen,
nor total protein synthesis was affected. These results suggest that
the observed reduction of the Hcy-induced elevation in collagen and
total protein synthesis by aqCbl is not the result of a toxic effect of
aqCbl. The Cbl-dependent enzyme methionine synthase catalyzes the
methylation of Hcy to regenerate methionine (Fig 1). CN-Hcy is
converted to aqCbl, which is a precursor of the Cbl II that is bound by
apo-methionine synthase (Fig 1). The conversion of CN-Cbl to aqCbl is
catalyzed by the ß-axial ligand transferase/Cbl reductase
complex,49 50 which, in SMCs, is irreversibly inhibited by
Hcy at a concentration of 20 µmol/L or higher and is
noncompetitively inhibited even below this concentration (E.H. Pezacka,
unpublished data, 1996). Adding aqCbl directly to SMC cultures,
however, eliminates the requirement for this enzyme's activity and
allows SMCs to overcome the metabolic block caused by
elevated Hcy concentrations.
In normal human serum, Cbl levels determined as CN-Cbl range from 0.15 to 0.81 nmol/L.51 The standard culture medium (DME/F12) used in these studies contained 500 nmol/L CN-Cbl, a level more than 600 times greater than physiological serum concentrations. Despite these high CN-Cbl concentrations, adding Cbl in the form of aqCbl inhibited Hcy enhancement of collagen synthesis. Recently Selhub et al19 have shown both the lack of correlation between plasma Hcy levels and vitamin B12 intake and that plasma Hcy levels decrease significantly after PLP or folate supplementation. This observation suggested that both PLP and folate, in contrast to CN-Cbl, may induce Hcy catabolism and remethylation, respectively. Our observations suggest that inhibition of the ß-axial ligand transferase/Cbl reductase complex by increased concentrations of Hcy explains, at least in part, the lack of correlation between CN-Cbl supplementation and decreased levels of Hcy in hyperhomocysteinemic patients. These results may also provide insight into potential preventive measures against Hcy-induced atherosclerosis.
Studies reporting the effect of Hcy on cultured cells frequently use both nonphysiological forms and concentrations of Hcy. Concentrations in the millimolar range, up to 10 mmol/L, have often been used, despite plasma concentrations of only 500 µmol/L in the most severe cases of hyperhomocysteinemia.5 6 7 8 9 Commercially available mixtures of the D and L enantiomers of Hcy have also been employed, although only the L form occurs naturally.2 A cyclic form of Hcy, Hcy thiolactone, has been used in other studies. This form has recently been identified as a byproduct of the proofreading function of methionyl-tRNA synthetase.52 However, the pathophysiological consequences of Hcy thiolactone formation still remain controversial; it is not readily detectable in serum because of rapid elimination both by enzymatic hydrolysis to Hcy and by attachment to proteins.53 54 55 In this study, L-Hcy, freshly prepared by the anaerobic alkaline hydrolysis of L-Hcy thiolactone,29 was used at concentrations consistent with plasma Hcy levels found in patients with pathophysiological hyperhomocysteinemia (50 to 500 µmol/L).
Hcy is structurally similar to D-penicillamine (ß,ß-dimethylcysteine) and, like penicillamine, has been reported to have lathyrogenic properties both in vitro and in vivo.56 57 58 In vitro, lathyrogens are frequently employed to inhibit cross-linking of collagen chains, which keeps newly synthesized collagen in a soluble form and prevents its accumulation in the cell layer. Despite this potential effect of Hcy, hydroxyproline analysis showed that SMCs exposed to Hcy accumulated nearly twice the amount of insoluble collagen as control cultures. Furthermore, patients with hyperhomocysteinemia do not display the vascular wall weakness59 that would result from a severe lack of collagen cross-linking. In the plasma of healthy humans, Hcy exists in two major forms: protein-bound and free homodisulfides or mixed disulfides. Plasma proteins have a maximal Hcy-binding capacity of about 150 µmol/L, and the protein-bound fraction accounts for about 70% to 75% of the total Hcy in plasma.60 The remainder may exist as Hcy-cysteine mixed disulfide or as a self-conjugate, homocystine. Less than 0.5% of total plasma Hcy exists in the free reduced form. Increased levels of both reduced free Hcy and homocystine are usually detected in the plasma of patients with hyperhomocysteinemia or homocystinuria, regardless of its cause.2 5 6 7 8 The increased free reduced form of Hcy, however, is insignificant compared with total plasma Hcy, and it is unlikely that the other forms are lathyritic.
Patients with hyperhomocysteinemia have a high incidence of thromboemboli, indicating enhanced thrombogenicity. Previous studies have shown that lathyritic collagen is more effective than normal collagen in aggregating platelets61 and that enhanced platelet deposition is correlated with areas enriched in collagen.62 Desquamation of endothelium by Hcy could temporarily expose the underlying extracellular matrix. The excessive collagen deposition and possibly partial inhibition of collagen cross-linking56 57 in hyperhomocysteinemic patients may alter the matrix, resulting in enhanced thrombogenic properties.
Hcy likely promotes atherogenesis by numerous mechanisms. It has been implicated in endothelial cell dysfunction and has been shown to denude vascular endothelium in vivo63 64 65 and to be cytotoxic to cultured endothelial cells.66 67 68 In contrast, SMC proliferation is stimulated by short-term exposure to Hcy.26 Our results showing enhanced proliferation in long-term cultures of Hcy-treated SMCs corroborate those reported by Tsai et al26 using short-term cultures, even at Hcy concentrations significantly lower than those tested in their studies and in the presence of high CN-Cbl concentrations. Hcy may promote the oxidation of LDL.42 69 Hcy may also play a role in atherosclerotic plaque formation through its potential involvement in generating free radicals.70 The mechanism by which hyperhomocysteinemia influences the excessive connective tissue production seen in occlusive vascular disease has not been established.
The results of our study, combined with previous findings concerning the effect of Hcy on endothelial cells and LDL, delineate possible mechanisms involving Hcy-induced atherosclerosis. It is the first evidence that Hcy at a concentration as low as 50 µmol/L enhances collagen production and accumulation by cultured SMCs. Further Hcy-dependent increases in collagen synthesis are dose dependent. Our data also suggest that Hcy may influence SMC participation in atherosclerosis in two ways. The initial effect would be to promote SMC proliferation and the second would be to promote a specific increase in collagen production and accumulation both in an absolute manner, expressed as collagen synthesis per SMC, and also as an increase relative to total protein synthesis. Administration of aqCbl to inhibit these effects may prove useful in preventing or slowing the progression of atherosclerosis. Current efforts in our laboratory are focused on determining the biochemical mechanisms by which Hcy increases cellular proliferation and upregulates collagen synthesis by SMCs, including Northern blot analysis of procollagen mRNAs, identification of signaling pathways, and identification of which specific forms of Hcy are eliciting its effects. In addition, we are investigating the effects of Hcy on other extracellular matrix components that are believed to be altered in patients with hyperhomocysteinemia.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grants DK42122 (to E.H. Pezacka) and HL29582 (to L.A. Ehrhart) and in part by Cleveland Clinic Foundation grant RPC No. 2813 (to E.H. Pezacka).
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Footnotes |
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Reprint requests to Alana Majors, Department of Human Genetics, Allegheny University of the Health Sciences, Allegheny Campus, Pittsburgh, PA 15212.
Received October 16, 1996; accepted December 11, 1996.
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References |
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