S-nitrosoalbumin-mediated relaxation is enhanced by ascorbate and copper: Effects in pregnancy and preeclampsia plasma

Magee-Womens Research Institute and Department of Environmental and Occupational Health, University of Pittsburgh, 204 Craft Ave, Pittsburgh, PA 15213, USA.
Hypertension (Impact Factor: 6.48). 01/2005; 45(1):21-7. DOI: 10.1161/01.HYP.0000150158.42620.3e
Source: PubMed


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 mumol/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.

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    • "Vitamin C, vitamin A, vitamin E, beta carotene, glutathione levels, and iron-binding capacity are lower in the maternal circulation of women with preeclampsia than women with a normal pregnancy. Gandley et al (2005) suggested that the higher circulating levels of S-nitrosoalbumin in women with preeclampsia reflect a deficiency in ascorbatemediated release of NO from S-nitrosoalbumin. These deficiencies in antioxidants may have important vascular effects in preeclampsia. "

    Preview · Article · Jul 2011
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    • "Furthermore, this report shows that nitrosoproteins breakdown in PE restores NO levels to those in NP. As suggested by others [3], impaired decomposition of S-nitrosoprotein during PE might explain, at least partially, the abnormal intracellular action of NO [4] "

    Full-text · Article · Apr 2006 · International Journal of Gynecology & Obstetrics
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    • "S-nitrosoproteins have been detected in many cell types including the endothelium [14]. The presence of increasing concentrations of reducing agents such as vitamin C and cysteine leads to the rapid release of NO and progressive decrease in detectable S-nitrosoproteins [14], [19], [25]. This process is enhanced by the presence of biologically relevant reduced transition metals such as copper and iron [24], [25]. "
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    ABSTRACT: Free nitric oxide (NO) reacts with sulphydryl residues to form S-nitrosothiols, which act as NO reservoirs. We sought to determine whether thiol-preserving agents and antioxidants, such as dithiothreitol (DTT) and vitamin C, induce NO release from S-nitrosylated proteins in endothelial cell cultures to promote angiogenesis. NO release was measured directly in cell supernatants using a Sievers NO Analyser, and in vitro angiogenesis was assessed by quantifying capillary-like tube network formation of porcine aortic endothelial cells (PAEC) on growth factor-reduced Matrigel. Incubation of PAEC with DTT or vitamin C significantly increased NO release in a concentration-dependent manner. However, the nitric oxide synthase (NOS) inhibitors, L-NNA and L-NIO, had no effect on DTT- or vitamin C-induced NO release, and there was no concomitant increase in the phosphorylation of endothelial NOS at serine-1177 following DTT or vitamin C treatment. DTT and vitamin C increased capillary-like tube network formation by nine- and two-fold, respectively, and the addition of copper ions doubled the effect of vitamin C. Surprisingly, DTT maintained endothelial tube networks for up to one month under serum-free conditions, and selective inhibitors of guanylyl cyclase (ODQ) and PKG (KT-5823) blocked this, demonstrating the requirement of cyclic GMP and PKG in this process. Both DTT and vitamin C are capable of releasing sufficient NO from S-nitrosothiols to induce capillary morphogenesis. This study provides the first evidence that increased denitrosylation leads to increased bioavailability of NO, independent of NOS activity, to promote sustained angiogenesis.
    Full-text · Article · Feb 2006 · PLoS ONE
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