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Cardiovascular Research 2001 50(3):583-588; doi:10.1016/S0008-6363(01)00208-5
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Copyright © 2001, European Society of Cardiology

Semicarbazide-sensitive amine oxidase catalyzes endothelial cell-mediated low density lipoprotein oxidation

Markus Exnera, Marcela Hermannb, Roland Hofbauera, Stylianos Kapiotisa,c, Peter Quehenbergera, Wolfgang Speisera, Irmtraud Heldd and Bernhard M.K Gmeinerd,*

aClinical Institute of Medical and Chemical Laboratory Diagnostics, University of Vienna, Vienna, Austria
bInstitute of Molecular Genetics, University of Vienna, Vienna, Austria
cDepartment of Laboratory Medicine, Hospital Neunkirchen, University of Vienna, Vienna, Austria
dInstitute of Medical Chemistry, University of Vienna, Vienna, Austria

* Corresponding author. Fax: +43-1-4277-60881 bernhard.gmeiner{at}univie.ac.at

Received 19 October 2000; accepted 11 January 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results and discussion
 References
 
Objective: Deamination products of semicarbazide-sensitive amine oxidases (SSAO), i.e. aldehydes, superoxide and ammonia have been shown to initiate vascular damage. SSAOs are copper-enzymes, present in endothelial (EC), smooth muscle cells (SMC) and in blood. Transition metals ions (Cu, Fe) mediate the oxidative (atherogenic) modification of LDL by SMC and EC. The physiological source of the active metal ions is still under debate. We hypothesize that SSAOs may catalyze LDL oxidation by endothelial cells via enzyme-complexed Cu++. Methods: EC isolated from human umbilical veins and cultured in 35 mm wells in RPMI-1640 medium were used as LDL oxidation system. Results: Diamine oxidase (DAO), a SSAO which activity is elevated in tissues and sera of diabetic patients, catalyzes the oxidation of LDL by EC. In the presence of purified DAO (0.07 to 70 U/l) LDL oxidation was increased up to 10-fold as measured by thiobarbituric acid reactive substance (TBARS) formation as well as apoprotein modification of LDL. Chemical blockage of the SSAO substrate binding site did not inhibit the catalytic effect of DAO on LDL oxidation. Denaturation of the enzyme did not destroy the ability of the preparation to facilitate LDL oxidation by EC. The potential of the enzyme to catalyze LDL oxidation was not suppressed in the presence of serum. However, selective removing of enzyme–copper completely abolished the ability of the enzyme to trigger cell-mediated LDL oxidation. Conclusion: DAO, beside generating angiopathic deamination products, has the potential to act as a pathophysiological catalyst of LDL atherogenic modification by vascular cells.

KEYWORDS Atherosclerosis; Lipoproteins; Endothelial function


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results and discussion
 References
 
There is now experimental evidence that the oxidative modification of LDL plays a pathophysiological role in the onset of atherogenesis [1,2]. This observation has led to studies dealing with the initiation of LDL oxidation by various stimuli. In general, lipid peroxidation can be initiated by, e.g. radicals like hydroxyl-, peroxyl-, tyrosyl-, tocopheryl- and O2. –/NO.. In addition, peroxidases, hypochlorite, transition metal ions (Cu, Fe) and vascular cells (in the presence of Cu or Fe ions) were found to alter the physicochemical and biological properties of the lipoprotein resulting in the formation of an atherogenic particle, inducing foam cell formation and initiating the early events of vessel wall alterations via chemoattractants [3–14].

However, with regard to the role and action of copper or iron ions in LDL modification, there is still a debate regarding the physiological source of catalytically active, i.e. copper. In this respect, copper and iron ions have been detected in atherosclerotic plaques [15]. Recently, it has been shown, that ceruloplasmin, the blood copper-transport protein, was able to facilitate the oxidation of LDL by vascular cells (EC and SMC) and under certain conditions in a cell-free system [16–19]. The lipid oxidizing potential of ceruloplasmin was strictly dependent on the copper content of the preparation, as the removal of copper abolished the catalytic activity [16,20]. These authors also reported that activated monocytic cells (U937) secrete ceruloplasmin and that this acute phase protein plays an important role in monocyte-mediated LDL oxidation [21]. Taken together, one can assume that ceruloplasmin can act as a physiological (pathological) catalyst of LDL atherogenic modification in the vascular system.

The deamination products of semicarbazide-sensitive amine oxidases (SSAO), i.e. aldehydes, ammonia and superoxide have been shown to attack vascular cells [22,23]. Excessive SSAO-mediated deamination as found in tissue and blood of diabetic patients may directly initiate endothelial injury, plaque formation, increase oxidative stress, and potentiate oxidative glycation [22,24]. As SSAOs are copper-containing enzymes [25], one may speculate, that this enzymes may have the potential to act as a catalyst in the oxidation reaction of LDL by vascular cells. Using purified diamine oxidase preparations as a model system for copper–SSAO we report, that SSAO can act as a catalyst in the endothelial cell-mediated oxidative modification of LDL similar to ceruloplasmin. Thus, SSAOs beside the generation of cytotoxic deamination products may, under certain conditions, facilitate LDL oxidation by vascular cells.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results and discussion
 References
 
2.1 Materials
Diamine oxidase (EC 1.4.3.6, from porcine kidney), semicarbazide hydrochloride and aminoguanidine hydrochloride were from Sigma. [1,4-14C] putrescine dihydrochloride (specific activity 107 mCi/mmol) was from Amersham Pharmacia UK. Chelex-100 resin was purchased from Bio-Rad Laboratories. All other chemicals used were of analytical grade.

2.2 LDL isolation
LDL was isolated by ultracentrifugation as reported previously [26]. The final preparation was dialyzed against 150 mmol/l NaCl containing 0.1 mmol/l EDTA and filter-sterilized. Protein concentration was estimated by a commercial test kit (Biorad). Results were obtained with seven different LDL preparations.

2.3 Endothelial cell culture
Endothelial cells (HUVEC) were isolated from human umbilical veins and maintained in culture as reported previously [27]. For experiments cells were passaged into 35 mm culture dishes. Only passage numbers 1 and 2 were used. All incubations were done in RPMI-1640 medium.

2.4 LDL oxidation
Before oxidation experiments, LDL was applied to a PD-10 column (Pharmacia BioTech) equilibrated with RPMI-1640 medium to get rid of EDTA. In all incubation reactions (see below) total protein concentration was kept constant at 1.2 mg/ml medium by addition of BSA.

2.4.1 Cell-mediated oxidation
When cell-mediated LDL oxidation was performed, HUVEC confluent monolayers were washed with RPMI-1640 medium and subsequently incubated with LDL (200 µg/ml) in RPMI-1640 for 24 h in the absence or presence of the respective compounds as given in the figure legends. Results were obtained with eight different HUVEC preparations.

2.4.2 Cell-free oxidation
LDL (200 µg/ml) was incubated in the absence or presence of the respective compounds in RPMI-1640 medium for 24 h as indicated in the figure legends.

2.5 Analysis of LDL oxidation
2.5.1 Thiobarbituric acid assay
LDL oxidation products were assayed as TBARS as described [26] using 1,1,3,3,-tetramethoxypropane as a standard.

2.5.2 Lipoprotein electrophoresis
Aliquots (10 µl) of treated or untreated LDL were applied to agarose gels (1% in veronal buffer) and run for 90 min and lipoproteins were detected according to the supplier of the analytical system (Lipidophor All In, Immuno-Baxter AG). Measurement of relative electrophoretic mobility (REM) was taken as an indicator of LDL oxidation [28], setting the electrophoretic mobility of native (untreated) LDL arbitrarily as one.

2.6 Treatment of diamine oxidase
2.6.1 Gel chromatography
Diamine oxidase (10 mg/ml) was applied to small Sephadex G-25 columns (Nick columns, Pharmacia BioTech) equilibrated in RPMI-16040 medium. The high molecular weight fraction was used in the cell-mediated LDL oxidation system.

2.6.2 Denaturation
Diamine oxidase (10 mg/ml) was denaturated by incubation in a boiling water bath for 3 min and after resuspension an aliquot of the preparation was used in the cell mediated LDL oxidation system.

2.6.3 Cofactor blockage
Diamine oxidase cofactor (pyridoxal) chemical modification was done by incubating the enzyme (10 mg/ml) in 0.15 mol/l NaCl with semicarbazide or aminoguanidine (20 mmol/l) for 60 min at 37°C and subsequently the enzyme was subjected to gel chromatography to get rid of unbound semicarbazide or aminoguanidine, respectively [22].

2.6.4 Copper removal
The enzyme solution (1 mg/ml in 0.15 mol/l NaCl) was treated with Chelex 100 resin for 24 h at 4°C subsequently centrifuged and the supernatant used in the cell-mediated LDL oxidation system.

2.7 Estimation of copper
Copper was estimated by atom absorption in an aliquot of a diamine oxidase solution (10 mg/ml in 0.15 mol/l NaCl) using a Perkin Elmer 5100 ZL atomic absorption spectrometer.

2.8 Determination of SSAO activity
SSAO activity was estimated by a radio-enzymatic procedure using 14C-labelled putrescine as substrate based on the method described by Okuyama and Kobayashi [29]. In brief, 0.2 ml of enzyme sample was supplemented with 5 µg/ml of 14C-labelled putrescine and incubated at 37°C for 60 min. After cooling to 4°C, sodium bicarbonate was added (about 200 mg/ml to give a final pH of 8) and putrescine reaction products were extracted into 1 ml of toluene and counted. One unit of enzyme activity is defined as one nanomole of product formed per minute per milligram of protein.


   3 Results and discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results and discussion
References
 
Semicarbazide-sensitive amine oxidases (SSAO) are copper enzymes which generate reaction products (aldehyde, superoxide, ammonia) that have been found to stress vascular cells leading to chronic angiopathy [22]. Elevated enzyme levels have been found in patients with diabetes and congestive heart failure (up to 1 U/l SSAO using benzylamine as substrate) [24,30] as well as in dialysis patients (up to 20 U/l DAO compared to about 5 U/l DAO in healthy controls using cadaverine as substrate) [31]. Taking into account, that copper ions can mediate LDL oxidation by endothelial cells, one may assume that SSAO via enzyme-complexed copper may have the potential to catalyze LDL oxidation by vascular cells. Fig. 1 shows the influence of increasing activities (0.07 to 70 U/l) of purified diamine oxidase (DAO) – which was used as a model enzyme for SSAO – on endothelial cell-mediated LDL oxidation. There was a concentration dependent increase of LDL oxidation observed and at the highest enzyme activity present in the medium about a 10-fold increase in LDL oxidation was monitored compared to controls. In contrast to the cell-mediated LDL oxidation only a modest lipid oxidation was recorded in the cell free system in the presence of DAO (see Fig. 1a). The increased TBARS formation in the presence of DAO found in HUVEC culture media was accompanied by an alteration of the relative electrophoretic mobility (REM) of LDL further indicating LDL atherogenic modification [28]. There was a concentration dependent increase in REM with increasing DAO activity present in culture medium leveling off at 50 U/l DAO, reaching about a two-fold REM value compared to controls (see Fig. 1b). To test that the catalytically active component, that is copper, is tightly bound to the enzyme preparation, DAO was subjected to column chromatography. Fig. 2 shows, that the extent of LDL oxidation by HUVEC in the presence of DAO (35 U/l) prior or after column chromatography of the enzyme was identical. Indicating that the catalytically active copper is tightly bound to the enzyme protein. To test if the enzyme's intact protein structure may be important for the observed catalytic effect, DAO preparations were subjected to heat denaturation. As seen in Fig. 2 heat denaturation did not diminish but even increase the catalytic effect of the preparation on HUVEC mediated LDL oxidation. Thus, one may assume that denaturation will release copper ions from the enzyme which are more catalytically active than enzyme-bound copper. Addition of an equivalent amount of free copper ions (0.44 µmol/l CuSO4) to the culture medium resulted in a similar increase in LDL oxidation by the cells as the addition of the denaturated DAO preparation containing the same molar concentration of copper as estimated by atom absorption (data not shown). DAO is sensitive to cofactor (pyridoxal) chemical blockage by aldehyde-reactive compounds like semicarbazide and aminoguanidine [32] resulting in inhibition of oxidase activity. As can be seen from Fig. 2 the blockage of the cofactor by both compounds did not influence the ability of the enzyme to facilitate cell-mediated LDL oxidation. However, diamine oxidase activity of the enzyme preparation was virtually completely inhibited by aminoguanide and semicarbazide pretreatment (3.4%±0.1 and 8.7%±0.5 of control, n=2). A result, further pointing to the central role of enzyme–copper in triggering the LDL oxidation by endothelial cells independent of the enzyme amine oxidase activity.


Figure 1
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  		Fig. 1 Influence of diamine oxidase on endothelial cell mediated LDL oxidation as estimated by TBARS formation and changes in relative electrophoretic mobility of LDL. Confluent HUVEC-cultures were incubated with LDL (0.2 mg/ml) in the presence or absence of increasing concentrations of purified diamine oxidase (DAO) for 24 h. Parallel incubations were run without endothelial cells. {circ} HUVEC, {blacksquare} no cells. (a) LDL oxidation was estimated as malondialdehyde (MDA) formed. Data from two different experiments±S.D. are given. (b) LDL relative electrophoretic mobility (REM) was estimated as given in Methods.

 

Figure 2
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  		Fig. 2 Influence of various treatments on the ability of diamine oxidase to catalyze endothelial cell mediated LDL oxidation. Confluent HUVEC-cultures were incubated with LDL (0.2 mg/ml) in the absence (control=100%; 0.303±0.026 µmol/L) or presence (1) of diamine oxidase (DAO) for 24 h after the following treatments, which are described in detail in Methods. Gel chromatography (2), denaturation (3), Chelex/copper removal (4), cofactor blockage (5,6), LDL oxidation was estimated as malondialdehyde (MDA) formed. Data from two different experiments±S.D. are given.

 
Treatment with Chelex-100 of proteins effectively removes divalent cations, especially copper, iron and zinc. When DAO was pretreated with Chelex-100 and the preparation was subsequently added to HUVEC cultures, DAO completely lost its ability to support HUVEC-mediated LDL oxidation (Fig. 2).

Proteins can exert non-specific antioxidant activity [33,34]. Therefore the influence of serum proteins on the observed DAO effect on cellular LDL oxidation was tested (Fig. 3). No inhibitory effect of serum (lipoprotein deficient) on the catalytic effect of DAO on LDL oxidation by HUVEC was observed in the concentrations (1 to 10% in RPMI-1640) tested.


Figure 3
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  		Fig. 3 Influence of serum on diamine oxidase catalyzed endothelial cell mediated LDL oxidation. Confluent HUVEC-cultures were incubated with LDL (0.2 mg/ml) in the presence of diamine oxidase (DAO, 70 U/l) with or without lipoprotein-deficient serum. LDL oxidation was estimated as malondialdehyde (MDA) formed. Data from two different experiments±S.D. are given.

 
Superoxide radicals are produced by vascular cells and this reactive oxygen species initiate LDL oxidation in the presence of metal ions or ceruloplasmin [13,16]. Aminoguanidine has been shown to inhibit cell-mediated lipoprotein oxidation [35] due to the ability of aminoguanidine (a drug which also prevents advanced glycation end-product formation in hyperglycemia) to scavenge superoxide radicals released from endothelial cells. As can be seen from Fig. 4a and b, the drug (0.125 to 10 mmol/l), when present in the cell culture medium, was very effective to inhibit the DAO facilitated cell-mediated LDL oxidation as monitored by TBARS formation and alteration in REM. It should be stressed that the cofactor blockade by itself by this compound completely suppressed amine oxidase activity but did not inhibit the catalytic activity of DAO in respect to cell mediated LDL oxidation (see above).


Figure 4
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  		Fig. 4 Influence of aminoguanidine on diamine oxidase catalyzed endothelial cell mediated LDL oxidation. Confluent HUVEC-cultures were incubated with LDL (0.2 mg/mL) in the presence of diamine oxidase (DAO, 70 U/l) with or without increasing concentrations of aminoguanidine. (a) LDL oxidation was estimated as malondialdehyde (MDA) formed. Data from two different experiments±S.D. are given. (b) LDL relative electrophoretic mobility (REM) was estimated as given in Methods.

 
One may speculate that EC-derived superoxide radicals (O2. –) may reduce DAO-bound Cu++ to Cu+ [36] thus facilitating LDL oxidation as Cu+ is known to be a critical factor inducing LDL lipid oxidation [3,37].

Our results demonstrate, that DAO supports endothelial cell-mediated LDL oxidation. This activity was restricted to the presence of enzyme–copper and independent of the intactness of the enzyme–substrate binding site (pyridoxal-cofactor). Thus, copper–SSAO not only generates vascular damaging deamination products [22,23], but may also contribute to angiopathy via their potential to act as a pathophysiological catalyst of LDL atherogenic modification by vascular cells. It is intriguing to speculate that the elevated DAO plasma activity found in dialysis patients may possibly contribute to the increased LDL oxidation reaction reported in these patients [38].

Time for primary review 20 days.


   Acknowledgements
 
We thank Claudia Müllner for expert technical assistance.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results and discussion
 References
 

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