Published online before print November 29, 2004, doi: 10.1161/01.HYP.0000150158.42620.3e
(Hypertension. 2005;45:21.)
© 2005 American Heart Association, Inc.
Scientific Contributions |
S-Nitrosoalbumin–Mediated Relaxation Is Enhanced by Ascorbate and Copper
Effects in Pregnancy and Preeclampsia Plasma
From the Magee-Womens Research Institute and Departments of Environmental and Occupational Health (R.E.G., V.A.T., W.H., A.A., J.J., B.P., C.A.H., V.E.K.) and Obstetrics, Gynecology, and Reproductive Sciences (A.D., G.H., C.A.H.), Center for Free Radical and Antioxidant Health (R.E.G., V.A.T., J.J., B.P.), University of Pittsburgh, Pittsburgh, Pa; and the Department of Obstetrics, Gynecology and Reproductive Sciences (R.N.T.), University of California, San Francisco.
Correspondence to Robin E. Gandley, PhD, Magee-Womens Research Institute, 204 Craft Ave, Pittsburgh, PA 15213. E-mail rsireg{at}mwri.magee.edu
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Abstract |
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S-nitrosoalbumin (SNO-Alb) is a major reservoir of releasable nitric oxide (NO) in plasma. In preeclampsia, a pregnancy-specific disorder associated with endothelial dysfunction, we previously found significant elevations in plasma SNO-Alb concentrations and decreased plasma ascorbate (Asc) levels. This increased SNO-Alb may result from low-plasma Asc if Asc, along with transition metals (eg, copper [Cu]) are necessary for release of NO from S-nitrosothiols. We propose that vasodilator effects of SNO-Alb, mediated by release of NO, are fully realized only when Asc/Cu availability is sufficient. Relaxation responses to SNO-Alb or the control reduced human serum albumin (SH-Alb), and responses to pooled plasma from normal or preeclamptic pregnancies were examined in isolated mouse arteries. Arteries preconstricted with phenylephrine were exposed to SNO-Alb or SH-Alb at physiologically relevant concentrations. When free Cu was added in excess (10 µmol/L), NO release was not dependent on Asc. However, when Cu was added at lower (physiological) levels, NO release was dependent on Asc. The addition of Asc and Cu to SNO-Alb stimulated vasodilatory responses in isolated arteries >90%, whereas no change in the SH-Alb (5%) response was observed. Preeclampsia plasma with higher levels of SNO-Alb caused arteries to relax 44.1±4.7%, whereas normal pregnancy plasma caused 11.9±4.2% relaxation (P=0.007). These data indicate that SNO-Alb alone or in plasma can act as a potent vasodilator, and that sufficient Asc/Cu promotes this action. We suggest that the higher circulating levels of SNO-Alb, in women with preeclampsia, reflect a deficiency in Asc/Cu-mediated release of NO from SNO-Alb.
Key Words: preeclampsia • pregnancy • nitric oxide • oxidative stress • antioxidants
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Introduction |
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Preeclampsia is a major cause of maternal and neonatal morbidity and mortality. The clinical manifestations of this pregnancy-specific disorder include hypertension and proteinuria developing after 20 weeks of gestation. Placental abnormalities and maternal endothelial dysfunction/activation are thought to contribute to vasospasm and the onset of the maternal syndrome. It has been hypothesized that oxidative stress plays a role in the pathophysiology of preeclampsia. Evidence of oxidative stress in combination with profound depletion of plasma ascorbate (Asc) has been reported in women with preeclampsia.1–4 Asc concentrations in women with preeclampsia are nearly half those of matched normal pregnant controls (
40 versus 25 µmol/L).5 The implications of this reduction in plasma Asc are currently not clear. Plasma Asc levels are inversely related to blood pressures in men without a history of hypertension.6,7 Asc and vitamin E supplementation in women at high risk for preeclampsia was associated with a reduction in markers of endothelial dysfunction and in the incidence of preeclampsia.5,8 Although the decreased incidence of preeclampsia was associated with decreased biochemical indices of oxidative stress and poor placental function, the mechanism(s) driving the apparent success of this treatment is currently unclear. With the onset of several large clinical trials examining this treatment regime during pregnancy, the role of Asc in the pathogenesis of preeclampsia and other pregnancy complications has become an exceedingly pertinent question. The potent vasodilator, nitric oxide (NO), is critical to normal vascular function and endothelial integrity. NO is important to the normal adaptive vasodilation of pregnancy in animals and women, and decreased NO bioavailability is thought to contribute to the development of preeclampsia.9 A functional loss of NO-mediated vasodilatation could result from decreased production by the endothelium, through improper storage, or oxidative degradation of NO and/or impaired vascular smooth muscle responsiveness to NO. There is substantial evidence of oxidative degradation of NO and increased levels of nitrosylated proteins in preeclampsia.1–4,10,11
Nitrosolated thiols in the plasma are a circulating source of stored NO, with the capacity to be released and have biological activity.12 Bioavailable reductants, such as Asc, in the presence of transition metals (eg, copper [Cu]) are required for release of biologically active NO from nitrosylated thiols.13 Cu in the presence of Asc is capable to undergoing 1-electron oxidation-reduction conversion. Reaction scheme typically includes the following reactions: 
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Formation of a Cu1+–S-nitrosoalbumin (SNO-Alb) intermediate weakens the S–N bond and strengthens the N–O bond, thereby promoting NO release from SNO-Alb.14 Serum albumin is an important carrier protein and buffer for redox active Cu in the circulation. Plasma Cu levels increase during pregnancy.15,16 We have previously reported that the Cu binding capacity of Alb is impaired in women with preeclampsia without an increase in the total circulating level.17 Total S-nitrosothiol and SNO-Alb concentrations were significantly increased in the plasma of these patients.10 Although increased NO synthesis could explain these increases, they alternatively might be caused by a decreased rate of decomposition of S-nitrosothiols in the plasma of women with preeclampsia. High S-nitrosothiol levels are associated with elevated blood pressure and cardiac events in patients with end-stage renal disease.18 It is biologically plausible that the increased reserve of SNO-Alb found in the plasma of women with preeclampsia occurs in part because of an oxidative stress-induced deficiency in plasma Asc. Previous in vitro data have suggested that the release of NO from SNO-Alb is limited in the absence of Asc or other suitable reductants.19 Therefore, we hypothesized that the vasodilatory effects of SNO-Alb would be maximized only when Asc/Cu availability is sufficient. In the current work, we have determined that SNO-Alb, the major nitrosothiol in the plasma, is a potent vasodilator when applied to isolated arteries. This vasodilatory activity is modulated by the reductant Asc and the presence of the transition metal Cu.
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Materials and Methods |
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Preparation of SNO-Alb
Nitrosylated human serum albumin (SNO-Alb) was prepared using the trans-nitrosylation reaction and S-nitrosoglutathione (GSNO) as an NO donor.20 GSNO was prepared by the reaction of acidified NaNO2 with glutathione. Briefly, 100 mmol/L glutathione was mixed with 100 mmol/L of NaNO2 in 200 mmol/L HCl.21 The solution was used fresh for S-trans-nitrosylation of reduced human serum albumin (SH-Alb). SH-Alb was mixed with a 50-fold excess of GSNO and low-molecular-weight components were removed.20,22 SH-Alb and SNO-Alb was quantified using Ellman reagent and DAF-2 assays, respectively, as previously described.23
Detection of NO Release From SNO-Alb
NO release was measured amperometrically using a Clark-type NO electrode (Iso-NO with 2-mm shielded sensor; WPI, Sarasota, Fla). Samples were incubated at room temperature in a reaction chamber under continuous stirring. Changes in current output (pA) were recorded, and NO release was quantified using a standard curve generated by the addition of NaNO2 in nitrite-free water under reducing conditions (KI/H2SO4). Initial rate of NO release from SNO-Alb was calculated as a difference in the amplitude of current for the first 30 seconds after addition of Cu/Alb. To simulate the isolated arterial bath conditions, NO release was measured in 3 mL of HEPES-buffered physiological saline solution (HEPES-PSS, pH 7.4) in the presence of a mesenteric artery.
Isolated Arterial Preparation
Small resistance-sized mesenteric arteries (150 to 200 µm) from female mice were removed, flushed of residual blood, and mounted in a dual-chamber pressurized arteriograph in HEPES-PSS.24 Transmural pressure and lumen diameters were monitored. Relaxation responses to modified albumin (SNO-Alb or SH-Alb) or 1% heparinized pooled plasma from patients with normal or preeclamptic pregnancies were assessed over a 15-minute period in phenylephrine (PE) preconstricted arteries. The concentration of Alb was matched to the level in 1% plasma, with a fraction of the Alb being SNO-Alb (5.8 µmol total Alb/L with 0.5 µmol SNO-Alb/L). Reduced human serum albumin (SH-Alb) was used to match the concentration of albumin relative to the level of nitrosylation of albumin, keeping the concentrations of both consistent. 1H-1,2,4 oxadiazolo (4,3-a)quinoxalin-1-one (ODQ; 10 µmol/L; Sigma), a guanylyl cyclase inhibitor, was used to block the relaxation pathway of NO. L-Nitro-arginine methyl ester (L-NAME; 0.25 mmol/L), an NO synthase inhibitor, was used to block endogenous production of NO in the isolated arteries. Asc and CuSO4 solutions were used at 50 µmol Asc/L and 0.25 or 10 µmol CuSO4/L buffer; 50 µmol Asc/L was chosen as a concentration comparable to that seen in the circulation5 (shown in Figure 1C) to maximize release of NO from SNO-Alb. Cu was added at both a limiting dose and in excess compared with the concentration of Alb present.
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Study Subjects and Sample Collection
Heparinized plasma was collected from a total of 10 nulliparous women with preeclampsia and 10 nulliparous women with uncomplicated pregnancies recruited at Magee-Womens Hospital in the third trimester of pregnancy, before labor or therapeutic intravenous administration of MgSO4. Preeclampsia was defined using the criteria of gestational hypertension, proteinuria, and hyperuricemia, and reversal of hypertension and proteinuria after delivery.25 Pregnant controls were normotensive throughout gestation, did not have proteinuria, and delivered at term. Pooled plasma samples from the 10 subjects in each group were prepared, aliquoted, and stored at –70°C.
Determination of SNO-Alb in Plasma by Biotin Switch Assay Using NitroGlo Kit
SNO-Alb in plasma was determined by Biotin Switch Assay using NitroGlo Kit (PerkinElmer Life Sciences). Briefly, free SH groups in plasma were blocked and proteins were precipitated by acetone. SNO-Alb was then reduced by Asc in the presence of HPDP–biotin, nonreducing buffer was added, and samples were electrophoresed (8% SDS-PAGE) and immunoblotted. SNO-Alb was quantified based on a calibration curve of biotinylated albumin.26
Statistical Evaluation
Two-way repeated measures ANOVA and post-hoc Bonferroni test or Student t test were used where applicable. Data in graphs are displayed as means±SE. Statistical significance was accepted if P<0.05.
More methods details are available in an online supplement at http://www.hypertensionaha.org.
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Results |
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Role of Asc in NO Release from SNO-Alb
NO release from in vitro nitrosylated human serum albumin (SNO-Alb; 0.5 µmol/L) was measured amperometrically in 3 mL HEPES-PSS. As indicated in Figure 1A, no release of NO was detected when SNO-Alb was diluted in HEPES-PSS. Furthermore, the addition of Asc (50 µmol/L) to this mixture did not elicit release of NO during short-term incubation. When excess (10 µmol/L) free Cu was subsequently added, a significant release of NO was detected. SH-Alb in the presence of Asc and Cu did not release detectable levels of NO (Figure 1A).
To further examine the role of Asc and Cu in the release of NO from SNO-Alb, the ratio of albumin to Cu was modulated. We assessed the requirement of Asc to recycle Cu back to its reduced form (Cu2+) for effective NO release to occur (Figure 1B). Alb is an important transporter of redox-active Cu in the circulation and binds Cu at a ratio of 1:1, avoiding the redox-cycling activity of the metal.27 Cu was added to fixed amount of SNO-Alb either in excess (2 Cu/Alb) or within the binding capacity (0.5 Cu/Alb) to establish conditions for Cu-mediated NO release (Figure 1B). At a ratio of 2 Cu/Alb, the release of NO was detected independently of the addition of Asc. The addition of Asc to this mixture resulted in a small additional release of NO. When the ratio of Cu/Alb was reduced to 0.5, the initial release of NO was very low, and only after the addition of 50 µmol/L Asc was a significant release of NO detected.
Increasing concentrations of Asc added to a fixed amount of S- NO-Alb (1 µmol/L) and Cu (0.5 µmol/L) increased the initial rate of NO release from SNO-Alb. SNO-Alb decomposition catalyzed by Cu/Alb (ratio 0.1:1) is strongly dependent on the concentration of Asc (Figure 1C). This dose-response established that at levels of Asc reported in plasma (µmol/L), Asc could modulate release of NO from SNO-Alb.
Dose-Response Effects of Nitrosylated Human Serum Albumin
Effects of the different Cu/Alb ratios on relaxation responses in the arterial myograph were examined. First, preconstricted arteries in the presence of a fixed concentration of SNO-Alb (0.5 µmol/L with a total of 5.8 µmol Alb/L) were exposed to 2 concentrations of Cu (Figure 2A). The percent relaxation of arteries exposed to 0.25 µmol/L Cu (Cu/Alb ratio of 0.05) was 50%, whereas arteries exposed to 10 µmol/L Cu (Cu/Alb ratio of 2) relaxed 70%, in line with our data on NO release from SNO-Alb. Reduced albumin (SH-Alb) used as a control verified that 10 µmol/L Cu had no vasoactive properties independent of SNO-Alb.
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SNO-Alb is a major reservoir for NO in plasma12 and is elevated in plasma from women with preeclampsia.10 To establish that SNO-Alb is capable of mediating dose-related vascular relaxation, the response of phenylephrine preconstricted arteries, in the presence of 50 µmol/L Asc and 0.25 µmol/L Cu, was assessed with increasing doses of SNO-Alb (Figure 2B). The arteries began to respond to SNO-Alb at submicromolar concentrations. For comparative purposes, the relaxation response to the potent NO donor, sodium nitroprusside, was also determined (Figure 2B). After completion of the dose-response experiment, additional NO release from albumin in buffer was undetectable by DAF2 assay, indicating that the release of NO from S- NO-Alb during the arterial response was complete.
To define the role of Asc in the relaxation response of SNO-Alb, we looked at the response of preconstricted arteries in the presence of 0.5 µmol/L SNO-Alb to the addition of the reductant Asc (50 µmol/L) in the presence of only trace amounts of transition metal (shown as Asc treatment; Figure 2C) relaxed 50%. After the addition of Asc, 0.25 µmol/L Cu (shown as Asc+Cu treatment) was added to the preparation (Figure 2C). If Cu (0.25 µmol/L) was also added to the buffer, relaxation was increased to >90% (P=0.022). No relaxation responses were observed in ODQ-treated arteries. To confirm that the observed vascular relaxation response was specific to SNO-Alb, preconstricted arteries were exposed to reduced albumin (SH-Alb) at a matching dose of total albumin. No relaxation response was observed on addition of Asc or Cu. Treatment of arteries with ODQ followed by SH-Alb was not significantly different from the response of SH-Alb alone (data not shown). We have further found that treating arteries with the NO synthase inhibitor, L-NAME, had no effect on this relaxation response. These data indicate that the nitrosylated albumin is acting as an NO donor, causing relaxation in isolated arteries.
Response of Preconstricted Isolated Arteries to Pooled Pregnancy Plasma
The amount of SNO-Alb in the plasma samples from the normal pregnancies and preeclampsia pregnancies was determined using the biotin switch assay. Biotinylated albumin standards were used to determine levels of SNO-Alb in the normal pregnancy pool (2.9 µmol/L) and the preeclampsia plasma pool (7.2 µmol/L) (Figure 3A inset). NO release from plasma pools was also measured (Figure 3A). The assay was validated using a pool of normal plasma with decomposed SNO-Alb (trace 2) or spiked with 2 µmol/L SNO-Alb (trace 3). The NO release detected in plasma from the normal pregnancy pool (trace 4) was approximately one-third that detected from the preeclampsia pool (trace 5), which had a signal comparable to the spiked normal pooled plasma (trace 3).
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Pooled normal pregnancy plasma or preeclampsia plasma (at a concentration of 1% plasma in buffer) was applied to preconstricted arteries supplemented with 50 µmol/L Asc buffer. Asc supplementation was used to achieve levels of Asc in both plasma samples sufficient to induce a maximal relaxation response based on data in Figure 1C. Consistent with their higher levels of SNO-Alb, preeclampsia plasma caused arteries to relax 44.1±4.7%, whereas normal pregnancy plasma caused 11.9±4.2% relaxation (n=4/group; P=0.007) (Figure 3B). Treatment with the guanylyl cyclase inhibitor (ODQ) prevented plasma-mediated relaxation responses. Pretreatment of arteries with the NO synthase inhibitor (L-NAME) had no effect on these relaxation responses (data not shown).
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Discussion |
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We found that SNO-Alb can act as a potent vasodilator provided sufficient amounts of Asc and Cu are available to promote this action. In vivo, Cu is normally bound to ceruloplasmin and albumin and maintained in a redox-inactive form. We previously found that modifications in Alb can impair the redox control of Cu and ultimately contribute to oxidative stress and depletion of Asc in the circulation of women with preeclampsia. Mishandling of Cu is caused by oxidative/nitrosative modifications in Alb, which are facilitated by excessive binding of free fatty acids.28–30 This modified Alb functions not as an antioxidant but as a pro-oxidant.17,27 We currently report that physiologically relevant concentrations of Asc will facilitate release of NO from SNO-Alb. SNO-Alb can act as a potent vasodilator in small isolated arteries, and adequate levels of Asc can facilitate both release and vascular relaxation. Cu at supra-physiological concentrations can cause release of NO from SNO-Alb independently of Asc. At much lower Cu concentrations (within the binding capacity of Alb), however, Asc enhances Cu-mediated NO release. Both NO release and/or trans-nitrosylation of low-molecular-weight thiols can be involved as the physiological mechanism by which SNO-Alb mediates its activity, as has been originally reported by Stamler.31 Under specific conditions of our experiments, however, the lack of exogenously added low-molecular-weight thiols make the latter mechanism unlikely. Because the presence of both Asc and Cu was essential for achieving maximal relaxation activity of SNO-Alb, we concluded that Asc-driven redox-cycling of Cu was the major contributing mechanism for its decomposition and NO· release. However, small relaxation response was also detectable in the absence of exogenously added Cu, indicating that some trans-nitrosation–dependent mechanism of Asc action32 might be responsible, at least in part, for its relaxation effects on mesenteric arteries.
Our data indicate that application of 1% plasma from women with preeclampsia to preconstricted arteries causes a greater relaxation response than plasma from women with normal pregnancies. This relaxation response was mediated through guanylyl cyclase and not by de novo generation of NO by the isolated artery. The finding of greater relaxation induced by preeclampsia plasma relative to normal pregnancy plasma is consistent with higher S-nitrosothiol levels (representing a source of potentially releasable NO) in preeclampsia.10 Our previous work indicated that the majority of the elevation in S-nitrosothiols in preeclampsia plasma was caused by SNO-Alb.10 The elevated levels of SNO-Alb in preeclampsia plasma represent a pool of NO with the potential to mitigate the profound vasoconstriction typically observed in this pathophysiological state. However, we cannot attribute the entire relaxation response to SNO-Alb because it is possible that the plasma samples have other contributing vasodilators (ie, estrogen, angiotensin 1 to 7 peptide).33,34
SNO-Alb at levels in the submicromolar range can induce relaxation in small isolated arteries. The sensitivity of the isolated mouse mesenteric arteries to SNO-Alb is within the dose range previously reported for SNO–bovine serum albumin applied to rabbit aortic strips.12 The levels obtained in the plasma pools used in this study are consistent with levels previously reported10,35 and may be an underestimate of the original levels in plasma, given the instability of SNO-Alb in biological samples.36 Methodological differences may be critical to the quantitative aspects of SNO-Alb analysis of endogenous levels. Using mild reducing conditions (provided by the addition of Asc) to detect the amounts of SNO-Alb in plasma by either the amounts of SH-Alb formed (biotin switch assay) or the amounts of NO released (using an NO·-sensitive electrode) yielded results in reasonable agreement. It should also be noted that the low-molecular-weight thiols present in our plasma samples represent a small portion of the total thiols.36 Asc and Cu, at the concentrations used, were not sufficient to induce vasorelaxation in the absence of SNO-Alb. When the Cu/Alb ratio is high, the requirement for Asc is less, likely because of the availability of free Cu. At low Cu/Alb ratios, Asc appears to allow redox cycling that enables the release of NO from SNO-Alb. We further showed that the guanylyl cyclase inhibitor ODQ inhibited the relaxation response, verifying that the NO signaling pathway mediates this effect. If arteries were exposed to SH-Alb, Asc, and/or Cu alone, no relaxation was observed.
The release of NO from SNO-Alb requires the presence of transition metal and reductant. Moreover, a Cu1+ chelator (neocuproine) produces concentration-dependent inhibition of the relaxations from S-nitrosothiols (GSNO, SNAP) in the rat anococcygeus muscle, which indicates that Cu1+ participates in the relaxant action of RSNO.37 Likewise, depletion of Asc levels (as result of Cu/Alb-catalyzed oxidation) has been shown to drastically decrease NO release from SNO-Alb and result in endothelial dysfunction.38 It is possible that profound conformational changes of Alb on binding of fatty acids—particularly in the presence of Cu tightly bound to its N-terminal tripeptide Asp-Ala-His site39 (located in a close proximity to S-nitrosylated Cys 34)—may lead to a decreased stability of its S–NO bond dissociation energy.32 In fact, we have recently reported that albumin/Cu/FA complexes exert dramatically increased rates of Asc-dependent SNO-Alb decomposition.40 We propose that the balance between Asc and Cu necessary for normal decomposition of SNO-Alb is lost in the setting of preeclampsia.
Perspectives
These data indicate that SNO-Alb can act as a potent vasodilator, and that sufficient Asc and Cu promote this action. It is likely that SNO-Alb, circulating at higher levels in preeclampsia plasma, represents a potential pool of NO. NO-mediated vasodilatory activity appears to be diminished in women with preeclampsia. Interventions to promote release of NO from SNO-Alb, such as Asc supplementation, might ameliorate the maternal and fetal vascular complications of this disease.
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Acknowledgments |
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Financial support received from National Institutes of Health grant numbers RO1 HL 64145, 2 PO1 HD 30367, 5M01 RR 00056, and HL 070807.
Received March 31, 2004; first decision April 16, 2004; accepted September 15, 2004.
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