(Circulation. 2000;102:2548.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Isolation and Characterization of Coenzyme A Glutathione Disulfide as a Parathyroid-Derived Vasoconstrictive Factor
From the Medizinische Klinik I, Universitäts-Klinik Marienhospital, Ruhr University of Bochum, Germany.
Correspondence to PD Dr H. Schlüter, Universitäts-Klinik Marienhospital der Ruhr-Universität Bochum, Hölkeskampring 40, 44625 Herne, Germany. E-mail hartmut.schlueter{at}ruhr-uni-bochum.de
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Abstract |
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Background—Coenzyme A glutathione disulfide (CoA-SSG) was recently isolated from bovine adrenal glands and was shown to be a renal vasoconstrictor. The identification of CoA-SSG in human parathyroid glands and its action on cultured vascular smooth muscle cells (VSMCs) are described here.
Methods and Results—After purification to homogeneity by several chromatographic steps, CoA-SSG was identified by matrix-assisted laser desorption/ionization mass spectrometry and enzymatic analysis. The dose-dependent growth-stimulating effect of CoA-SSG on VSMCs, measured by the [3H]thymidine method, is characterized by a threshold of 10-8 mol/L and a maximum effect of 10 µmol/L, increasing VSMC proliferation 254±21% above control. A dose of 10 µmol/L methylmalonyl-CoA and 10 µmol/L CoA increased the rate of proliferation of VSMCs only by 178±43% and 50±42% above control, respectively. Glutathione has no proliferative effect on VSMCs. The growth-stimulating effect of CoA-SSG (1 µmol/L) was decreased by the antagonists 3,7-dimethyl-1-propargylxanthine (DMPX; 11 µmol/L) (38% compared with CoA-SSG without antagonist) and pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (PPADS; 10 µmol/L) (48% compared with CoA-SSG without antagonist; each P<0.05 versus control), indicating that the effect is mediated partly via A2 and partly via P2Y1 and/or P2Y4 receptor.
Conclusions—CoA-SSG may play a regulatory role in VSMC growth as a progression factor and thereby could play an important role in development of hypertension.
Key Words: enzymes • muscle, smooth • cells
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Introduction |
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The parathyroid glands have long been supposed to contain a yet unidentified vasoactive hormone. Pang et al1 and others2 showed that extracts of parathyroid glands from spontaneously hypertensive rats elicited vasoconstriction in several experimental models.
However, the so-called "parathyroid hypertensive factor" (PHF) has not yet been successfully identified. Interestingly, the PHF was shown to contain both peptide3 and nonpeptide components. Because convincing parathyroid-derived factor had been presented by those authors, we were interested in whether human parathyroid glands contain a recently identified vasoconstrictive substance, coenzyme A glutathione disulfide (CoA-SSG). In an earlier study, we isolated CoA-SSG from bovine adrenal glands and showed that this substance is a potent vasoconstrictor.4 In addition to its vasoactive action, the substance potentiates the effects of angiotensin II on vascular tone.
In the present study, we demonstrate that CoA-SSG is also found in human parathyroid glands. There is some probability that CoA-SSG is identical with the PHF, the existence of which had been shown only indirectly in earlier studies.
Furthermore, we extend our knowledge of the physiological action of CoA-SSG with respect to vascular smooth muscle cell (VSMC) growth. This may be of interest, because disturbances in VSMC growth are known to play an important role in cardiovascular disorders such as hypertension and atherosclerosis.5 6 The pathogenesis of hypertension is a process that involves both enhanced vasoconstriction5 and the remodeling of the arterial wall,7 which is characterized by hypertrophy and proliferation of VSMCs. Furthermore, it appeared likely that CoA-SSG exhibits not only vasoconstrictive but also proliferative actions, because several vasoconstrictors, such as angiotensin II,8 thromboxane,9 and ATP,10 are known to be potent VSMC growth factors as well.
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Methods |
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All reagents were purchased from Sigma Chemical Co unless otherwise specified. Human parathyroid glands were obtained from patients undergoing parathyroidectomy for parathyroid adenoma or hyperplasia due to secondary or primary hyperparathyroidism. In all patients with secondary hyperparathyroidism, end-stage renal disease was present. The study was approved by the local ethical committee, and written consent was obtained from the patients. For isolation of CoA-SSG, only macroscopically intact tissue was used.
Purification of CoA-SSG From Human Parathyroid Gland
Tissue
After excision from the patients, human parathyroid gland tissue
(
2 g) was immediately placed in ice-cooled
physiological saline solution and processed within
30 minutes.
The following isolation procedure was designed to exclusively
isolate CoA-SSG from human parathyroid glands. The human parathyroid
gland tissue was cut into small pieces (1
cm3), frozen in liquid nitrogen, and stored at
-80°C for 1 night. Then the tissue was lyophilized and powdered
(step 1). The powder was suspended in 20 mL 0.6 mol/L ice-cold
perchloric acid and homogenized at 25 000 rpm 10 times for
30 seconds. The homogenate was ultracentrifuged at
30 000 rpm for 60 minutes at 4°C. The supernatant was adjusted with
KOH to pH 8.5 and stored at 4°C for 30 minutes to precipitate
KClO4. After centrifugation at
4000 rpm for 10 minutes at 4°C, the supernatant was titrated to pH
6.5 with HCl and centrifuged again as above (step 2).
Preparative Reversed-Phase Chromatography
Extract of the human parathyroid gland tissue was concentrated
on a C18 reversed-phase column (LiChroprep, 310x65 mm, 65 to
40 µm, Merck) with 40 mmol/L aqueous triethylammonium
acetate (TEAA) in water (flow rate 2 mL/min). After nonbinding
substances had been removed with aqueous 40 mmol/L TEAA, the
remaining substances were eluted with 20% acetonitrile in water
(flow rate 2 mL/min) (step 3). The elution was detected by UV
absorption at 254 nm. The eluate was lyophilized and stored frozen at
-80°C.
High-Performance Liquid-Displacement Chromatography
The lyophilized eluate of the preparative reversed-phase
chromatography was dissolved in aqueous 40 mmol/L
TEAA solution and injected onto a C18 reversed-phase column
(Supersphere, 2.1x100 mm, 4 µm, Merck; step 4) that was
equilibrated with aqueous 40 mmol/L TEAA as carrier as before. The
carrier was pumped through the system at a flow rate of 50 µL/min
during injection of the sample.
After the injection was finished, n-butanol (100 mmol/L) in 40 mmol/L TEAA was used as displacer (flow rate 50 µL/min). The displacement chromatography was monitored by UV absorption at 254 nm. The fraction size was 100 µL. Every fraction of the displacement chromatography was lyophilized and then further separated by anion-exchange chromatography.
Anion-Exchange Chromatography
Lyophilized fractions of the displacement
chromatography were dissolved in 1 mL 20 mmol/L
K2HPO4 in water (pH 8)
(eluent A) and chromatographed by use of an anion exchanger
(step 5) (column: Mono Q HR 5/5, 50x5 mm, 10 µm, Pharmacia
Biotech; eluent B: 20 mmol/L
K2HPO4 and 1 mol/L NaCl
[pH 8] in water; gradient: 0 to 10 minutes: 0% to 5% B; 10 to 115
minutes: 5% to 40% B; 115 to 120 minutes: 40% to 100% B; flow rate:
0.1 mL/min; UV absorption wavelength: 254 nm).
Reversed-Phase Chromatography
Each peak of the anion-exchange chromatography
with a retention time comparable to the retention time of authentic
CoA-SSG was desalted by high-performance reversed-phase C18
liquid chromatography (step 6). The reversed-phase
column (Supersphere, 250x4 mm, 4 µm, Merck) was
equilibrated with 40 mmol/L aqueous TEAA in water. The sample
dissolved in the same eluant was pumped with a flow rate of 0.5 mL/min
onto the column. After the column had been washed with 10 mL 40
mmol/L TEAA in water, the substances were eluted with 35% acetonitrile
in water at a flow rate of 0.5 mL/min. The resulting fractions were
lyophilized.
Matrix-Assisted Laser Desorption/Ionization Mass
Spectrometry
The lyophilized fractions with a significant UV absorption at
254 nm from the reversed-phase chromatography were
examined by matrix-assisted laser desorption/ionization mass
spectrometry (MALDI-MS) and postsource decay (PSD)-MALDI-MS. A
reflector-type time-of-flight mass spectrometer (Reflex III, Bruker)
was used according to Hillenkamp and Karas.11 The sample
was mounted on an x, y, z movable
stage allowing irradiation of selected sample areas. In this study, a
nitrogen laser (VSL-337 ND, Laser Science) with an emission wavelength
of 337 nm and 3-ns pulse duration was used. The laser beam was focused
to a diameter of typically 50 µm at an angle of 45° to the
surface of a target. Microscopic sample observation was possible. Ten
to 20 single spectra were accumulated for a better signal-to-noise
ratio. In MALDI-MS, large fractions of the desorbed analyte ions
undergo PSD during flight in the field free drift path. With a
reflector-type time-of-flight setup, sequence information from PSD
fragment ions of precursors produced by MALDI were
obtained.12 Sample preparations for MALDI and
PSD-MALDI experiments were identical. The concentrations of the
analyzed substances were 1 to 10 µmol/L in bidistilled
water. Analyte solution (1 µL) was mixed with 1 µL of matrix
solution (50 mg/mL 3-hydroxy-picolinic acid in water). To this mixture,
cation exchange beads (AG 50 W-X12, 200 to 400 mesh, Bio-Rad)
equilibrated with H+ as counterion were added to
remove Na+ and K+ ions. The
mixture was gently dried on an inert metal surface before introduction
into the mass spectrometer. The mass accuracy was in the range of
0.01%.
Enzymatic Analysis and Reduction With
Mercaptoethanol
To test for the presence of disulfide bonds, 5 µL of the
fraction was incubated with 1 µL glutathione reductase (EC 1.6.4.2,
Type VII, Sigma; 10 mU/L) at room temperature for 30 minutes. In
addition, 5 µL of the fraction was boiled with 5 µL mercaptoethanol
for 20 minutes. The split products were identified by their
molecular masses with the use of MALDI-MS and PSD-MALDI-MS,
respectively.
Effect of CoA-SSG on Rate of Proliferation of VSMCs
Aortic VSMCs from normotensive Wistar-Kyoto rats were
subcultured in 96-well dishes (Falcon) at a density of
5x104 cells/mL and kept in culture medium
containing 10% FCS to reach a subconfluent monolayer. After 24 hours,
the cells were growth-arrested in 0.1% FCS for 48 hours without
affecting cell adherence to culture wells or viability as checked by
trypan blue vital dye exclusion.
Quiescent VSMCs were then exposed to fresh culture medium with 0.1% FCS with CoA-SSG, CoA, methylmalonyl–coenyzme A, and glutathione for a 48-hour incubation period. Moreover, in the presence of CoA-SSG, the receptor antagonist pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (PPADS, 10 µmol/L) and as a potent and selective A2 antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 11 µmol/L)13 14 were added to the culture medium. Cell proliferation was measured by use of the [3H]thymidine incorporation rate as described elsewhere.15
Control Experiment: Incubation of CoA and Glutathione in the
Presence of Perchloric Acid
CoA 1 µmol and glutathione 1 µmol were dissolved
in 20 mL water. Perchloric acid was added to a final concentration of
0.6 mol/L. The sample was treated like the tissue extract described
above. The supernatant passed the same chromatographic
steps as described above. Fractions from the last
chromatographic step with a significant UV absorption were
analyzed by MALDI-MS.
Statistical Analysis
The data were expressed as mean±SEM. The data of the
proliferation experiments were analyzed by ANOVA. Statistical
significance was assumed to be 2-tailed if P<0.05.
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Results |
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Figure 1A
shows the chromatogram of
a reversed-phase displacement chromatography with TEAA
as an ion-pair reagent of the human parathyroid gland extract after
extraction with perchloric acid and concentration on a reversed-phase
chromatography gel. CoA-SSG eluted within 88 to 90
minutes, labeled in the figure by an arrow and a gray bar.
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Each fraction of the displacement chromatography
with a significant UV absorption at 254 nm underwent anion-exchange
chromatography (step 5; Figure 1B
). Each
fraction of the anion-exchange chromatography with a
retention time comparable to that of CoA-SSG was desalted by
reversed-phase chromatography (step 6). This
lyophilized eluate of the reversed-phase chromatography
fraction was subjected to the analytical procedures described
below.
First, the molecular mass of the substance underlying the peak of the reversed-phase chromatography with a retention time comparable to that of authentic CoA-SSG was determined by MALDI-MS as 1073.4 Da (1074.6 Da=[M+H]+).
Figure 2 shows the corresponding
PSD-MALDI mass spectrum of the desalted fraction of anion-exchange
chromatography, labeled by an arrow in Figure 1B. The fragmentation pattern of the isolated substance obtained
by this PSD-MALDI mass spectrum was identical to that from commercially
available CoA-SSG.
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Figure 3 shows the MALDI mass
spectra of the isolated fraction before (Figure 3A) and after
(Figure 3B) incubation with glutathione reductase, indicating
the presence of glutathione in the molecule and a disulfide bond of CoA
and glutathione. Boiling with mercaptoethanol yields an identical MALDI
spectrum.
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To prove whether perchloric acid may oxidize CoA and glutathione, resulting in CoA-SSG, both substances were incubated with perchloric acid. The mixture passed the same purification procedure as the tissue extract. With MALDI-MS, no CoA-SSG was detectable.
CoA-SSG induced a dose-dependent increase in DNA synthesis in
VSMCs, as determined by [3H]thymidine uptake
(Figure 4). The threshold of the
growth-stimulating effect of CoA-SSG was
10-8 mol/L. The maximum
effect was obtained at CoA-SSG concentrations of 10 µmol/L,
which increased VSMC proliferation 254±21% above control.
Methylmalonyl-CoA 10 µmol/L as well as CoA 10
µmol/L increased the rate of proliferation to 178±43% and 50±42%,
respectively, above control. As shown in Figure 4, significant
effects on the proliferation rate of VSMCs were observed with 10 nmol/L
CoA-SSG. Glutathione had no effect on the rate of proliferation of
VSMCs. The threshold concentration for the direct growth-stimulatory
effect of CoA-SSG and methylmalonyl-CoA was
10-8 mol/L, and for that
of CoA 10-7 mol/L. The
EC50 value (in log mol/L) of CoA-SSG was
-8.48±0.15, that of methylmalonyl-CoA -8.15±4.3, and that of CoA
-7.41±0.48.
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), methylmalonyl-CoA (
), and CoA
(
). Ordinate shows rate of [3H]thymidine incorporation
in percent above control (0.1% FCS); data are mean±SEM from 10
independent experiments.
The growth-stimulatory effect of CoA-SSG was inhibited by 2
different purinoceptor antagonists (Figure 5). In the presence of 11
µmol/DMPX blocking the A2 receptor, the rate of
proliferation decreased 38% compared with CoA-SSG alone
(P<0.05 versus control). The growth-stimulating effect
induced by CoA-SSG was, moreover, significantly inhibited by the
P2 antagonist PPADS (rate of
proliferation [% above control], CoA-SSG versus CoA-SSG+PPADS:
469±59 versus 244±71 [P<0.05 versus control]) (Figure 5).
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Discussion |
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In the parathyroid gland, several known and unknown vasoactive hormones exist. The parathyroid hormone (PTH) causes dose-dependent transient vasodilatation in various vascular beds.16 Rat parathyroid cells were shown to synthesize and secrete endothelin I.17 In many studies, parathyroidectomy was demonstrated to decrease blood pressure.18 19 20 In patients who were hypertensive before operation, both the systolic and diastolic blood pressure significantly decreased after parathyroidectomy.21 Therefore, the existence of a vasopressor in human parathyroid glands possibly responsible for the development of primary hypertension is discussed. Pang et al1 suggested a parathyroid gland–derived hypertensive factor (PHF) according to the observation that parathyroidectomy decreased mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHR) and resulted in the disappearance of the hypertensive factor from the plasma. Transplantation of SHR parathyroid glands into Sprague-Dawley rats resulted in an increase in MAP and the appearance of the factor in the plasma, whereas transplantation of Sprague-Dawley parathyroid glands into SHR had exactly the opposite effect. Sprague-Dawley to Sprague-Dawley transplantation had no effect on MAP or hypertensive factor activity.22 In a further study, it was assumed that parathyroid gland can express PHF in humans and that such expression may be responsible for a proportion of the high reported incidence of hypertension in primary hyperparathyroidism.23 After partial characterization, the structure of the PHF was suggested to be a peptide linked to a lysophospholipid.3
In this study, we were able to isolate and identify CoA-SSG from human parathyroid glands, which was identified earlier from bovine adrenal glands.4 There is some probability that the substance isolated from human parathyroid glands by Schlüter et al24 in 1992 may be attributed to CoA-SSG.
From experiments in adrenal glands, it is known that CoA-SSG can be released by stimulation with carbachol4 or A23187.25 From these findings, it can be inferred that both an increase in cytosolic free Ca2+ concentration and cholinergic stimulation of adrenal medulla are important mechanisms of CoA-SSG release. For parathyroid gland tissue, however, these mechanisms can only be inferred by analogy at present.
Vascular actions of CoA-SSG have been demonstrated in previous studies. CoA-SSG has a direct effect on the renal vascular resistance. Intra-aortic injections of CoA-SSG increase blood pressure in intact animals.4 The vasopressor effect of CoA-SSG was demonstrated in both renal and mesenteric vasculature. CoA-SSG contracts renal vasculature, increases systemic blood pressure, and increases [Ca2+]i in VSMCs. Furthermore, with respect to the vasculature, an interesting interaction with angiotensin II was noted: The vasoconstrictor effect of angiotensin II on renal vasculature was potentiated in the presence of CoA-SSG.4
Is the PHF identical with CoA-SSG? Obviously, this question cannot be decided definitively at present. There are several similarities between the 2 agents, such as the peptide and nonpeptide moiety.26 In contrast, the hypertensive action of PHF is much more delayed and prolonged than that of CoA-SSG. However, the indirect effects of CoA-SSG, potentiating the vasoconstrictive effects of angiotensin II, show a latency similar to the vascular effect of PHF. With respect to both similar and different properties of the 2 agents, it may also be considered whether PHF is a derivative of CoA-SSG. Furthermore, it must be remembered that rat and human parathyroid glands may produce similar, but not identical, vasoactive factors. PHF has not been demonstrated in human parathyroid glands, and conversely, we did not examine rat parathyroid tissue.
At present it is not known whether CoA-SSG is produced or secreted in increased amounts in parathyroid adenomas or hyperplastic parathyroid glands. Several clinical observations may support a role of CoA-SSG in human pathology. First, primary hyperparathyroidism is accompanied by an increase in blood pressure, although PTH is a vasodilator.27 Given that part of the vascular changes in primary hyperparathyroidism are due to elevated serum Ca2+ levels, an increased secretion of CoA-SSG may present an alternative explanation for this clinical finding unexplained by PTH. Second, parathyroid hyperplasia in renal failure could lead to an increased release of CoA-SSG. Although PTH has been postulated to act as a uremic toxin,28 several features of uremic toxicity, such as neurotoxicity and the cardiovascular uremic changes, could never be thoroughly explained by the physiological actions of PTH. Therefore, it may be speculated that CoA-SSG could also play a role in secondary hyperparathyroidism, although at present, firm data are lacking.
In addition to the vasopressor properties of CoA-SSG, the results
of the proliferation assay show that CoA-SSG has a direct effect on the
rate of proliferation of VSMCs. The dose-dependent growth-stimulating
effect of CoA-SSG is obviously determined by the CoA component of
CoA-SSG (Figure 4) and not by the glutathione component.
Glutathione amplifies the growth-stimulating effect of the CoA
component of CoA-SSG. The stimulating effect of CoA-SSG is mediated by
a receptor that recognizes CoA.
As shown in Figure 5, the growth-stimulating effect of
CoA-SSG is partially inhibited by the potent and selective
A2 antagonist DMPX13 as
well as by the P2 antagonist
PPADS.29 Because the P2X receptor is
not involved in cell proliferation and, moreover, this receptor subtype
is lost in cultured VSMCs,10 it seems reasonable that the
mitogenic effect of CoA-SSG is mediated by the
P2Y receptor. Because only the
P2Y1 and
P2Y4 subtypes of the
P2Y receptor are inhibited by
PPADS,30 31 it seems likely that the growth-stimulating
effect of CoA-SSG is mediated by these P2
receptor subtypes. Both the sigmoidal concentration-dependency of the
effects and the specific blockade by purinoceptor
antagonists make a nonspecific proliferative effect rather
unlikely.
The role of CoA-SSG in the regulation of vasomotor tone and growth is still largely speculative. First, the adequate stimulus to release CoA-SSG from an endocrine organ has not been defined. With respect to adrenal medulla, sympathetic stimulation may be one mechanism of release, because CoA-SSG has been found in exocytotic granules together with catecholamines.4 In parathyroid gland, the stimulus of CoA-SSG release is much more difficult to define, because we do not know whether calcium or phosphate homeostasis can affect CoA-SSG release in a manner similar to that of PTH. Nevertheless, some data indicate a role of parathyroid glands in vascular control. For example, calcium intake is known to affect blood pressure.32 This observation, among others, led to the concept of a PHF.33 From its biological properties, CoA-SSG can clearly be regarded as a parathyroid-derived hypertensive substance.
In summary, the findings show that human parathyroid glands contain a vasoconstrictive factor, as was suggested from studies in rat parathyroid tissue. In addition to its vasoconstrictive action, CoA-SSG also acts as a growth factor in VSMCs.
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft Schl 406/1–2. We thank A. Pacha for valuable technical assistance.
Received March 21, 2000; revision received May 23, 2000; accepted June 8, 2000.
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