Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin

Key points Nitric oxide (NO) is a gasotransmitter with important physiological and pathophysiological roles in pregnancy. There is limited information available about the sources and metabolism of NO and its bioactive metabolites (NOx) in both normal and complicated pregnancies. The present study characterized and quantified endogenous NOx in human and mouse placenta following determination of the stability of exogenous NOx in placental homogenates. NOx have differential stability in placental homogenates. NO and iron nitrosyl species (FeNOs), are relatively unstable in placental homogenates from normal placentas. Exogenous NO, nitrite and nitrosothiols react with placental homogenates to form iron nitrosyl complexes. FeNOs were also detected endogenously in mouse and human placenta. NOx levels in placental villous tissue are increased in fetal growth restriction vs. placentas from women with normal pregnancies, particularly in fetal growth restriction associated with pre‐eclampsia. Villitis was not associated, however, with an increase in NOx levels in either normotensive or pre‐eclamptic placentas. The results call for further investigation of FeNOs in normal and complicated pregnancies. Abstract Nitric oxide (NO) is a gasotransmitter with important roles in pregnancy under both physiological and pathophysiological conditions. Although products of NO metabolism (NOx) also have significant bioactivity, little is known about the role of NO and NOx under conditions of aberrant placental inflammation during pregnancy. An ozone‐based chemiluminescence approach was used to investigate the stability and metabolic fate of NOx in human placental homogenates from uncomplicated pregnancies in healthy mothers compared to that in placental tissue from normotensive and pre‐eclamptic pregnancies complicated with fetal growth restriction (FGR) with and without villitis of unknown aetiology. We hypothesized that placental NOx would be increased in FGR vs. normal tissue, and be further increased in villitis vs. non‐villitis placentas. Findings indicate that nitrate, nitrite and nitrosothiols, but not NO or iron nitrosyl species (FeNOs), are relatively stable in placental homogenates from normal placentas, and that NO, nitrite and nitrosothiols react with placental homogenates to form iron nitrosyl complexes. Furthermore, NOx levels in placental villous tissue are increased in FGR vs. placentas from women with normal pregnancies, particularly in FGR associated with pre‐eclampsia. However, in contrast to our hypothesis, villitis was not associated with an increase in NOx levels in either normotensive or pre‐eclamptic placentas. Our results also strongly support the involvement of FeNOs in both mouse and human placenta, and call for their further study as a critical mechanistic link between pre‐eclampsia and fetal growth restriction.

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“…2015; Liu et al . 2018; Mukosera et al . 2018) and other groups have reported the same in vascular tissue (Mülsch et al .…”

Section: Resultsmentioning

confidence: 99%

Nitric oxide metabolism in the human placenta during aberrant maternal inflammation

Mukosera

Clark

Ngo

et al. 2020

The Journal of Physiology

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“…The reaction with superoxide anion to form peroxynitrite (ONOO‐) is a physiological process that can convey the GSNO‐derived NO in the extracellular fluid than contributing to control the physiological levels of this bioactive gas and signaling molecule in tissues. For example, these properties may help to explain the in vitro and in vivo vasodilation properties of GSNO that are not observed in the case of other pharmacological and inorganic NO donors .…”

Section: Introductionmentioning

confidence: 99%

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways

et al. 2018

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Glutathione is considered the major non‐protein low molecular weight modulator of redox processes and the most important thiol reducing agent of the cell. The biosynthesis of glutathione occurs in the cytosol from its constituent amino acids, but this tripeptide is also present in the most important cellular districts, such as mitochondria, nucleus, and endoplasmic reticulum, thus playing a central role in several metabolic pathways and cytoprotection mechanisms. Indeed, glutathione is involved in the modulation of various cellular processes and, not by chance, it is a ubiquitous determinant for redox signaling, xenobiotic detoxification, and regulation of cell cycle and death programs. The balance between its concentration and redox state is due to a complex series of interactions between biosynthesis, utilization, degradation, and transport. All these factors are of great importance to understand the significance of cellular redox balance and its relationship with physiological responses and pathological conditions. The purpose of this review is to give an overview on glutathione cellular compartmentalization. Information on its subcellular distribution provides a deeper understanding of glutathione‐dependent processes and reflects the importance of compartmentalization in the regulation of specific cellular pathways. © 2018 BioFactors, 45(2):152–168, 2019

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“…Dinitrosyl-iron complexes (DINICs) are the derivative of nitric oxide (NO), iron, and other ligands. They play a crucial role in stabilization, storage, and NO bio-activity [ 152 ]. The electron paramagnetic resonance (EPR) signal at g = 2.03 is a characteristic feature of DINICs and was identified in vivo in animal tissues and other organisms [ 153 ].…”

Section: Other Glutathione-iron Complexesmentioning

confidence: 99%

“…DINICs complexed with glutathione may also be of interest for therapeutic applications [ 153 ]. They might serve also as ·NO donors to regulate the muscle tonus around the vasculature [ 152 ] and have already been successfully tested as hypotensive drugs in clinical trials [ 166 ]. The stability of DINICs can be increased through their interaction with proteins [ 153 ].…”

Section: Other Glutathione-iron Complexesmentioning

confidence: 99%

“…The stability of DINICs can be increased through their interaction with proteins [ 153 ]. For example, cysteinyl residues in serum albumin can modulate and prolong the vasodilating activity of glutathionyl-DINICs [ 152 ]. It is noteworthy that these DINICs do not seem to affect the cellular glutathione levels, nor cellular proliferation [ 167 ].…”

Section: Other Glutathione-iron Complexesmentioning

confidence: 99%

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Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism—Review

et al. 2020

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Glutathione (GSH) was initially identified and characterized for its redox properties and later for its contributions to detoxification reactions. Over the past decade, however, the essential contributions of glutathione to cellular iron metabolism have come more and more into focus. GSH is indispensable in mitochondrial iron-sulfur (FeS) cluster biosynthesis, primarily by co-ligating FeS clusters as a cofactor of the CGFS-type (class II) glutaredoxins (Grxs). GSH is required for the export of the yet to be defined FeS precursor from the mitochondria to the cytosol. In the cytosol, it is an essential cofactor, again of the multi-domain CGFS-type Grxs, master players in cellular iron and FeS trafficking. In this review, we summarize the recent advances and progress in this field. The most urgent open questions are discussed, such as the role of GSH in the export of FeS precursors from mitochondria, the physiological roles of the CGFS-type Grx interactions with BolA-like proteins and the cluster transfer between Grxs and recipient proteins.

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Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin

Cited by 27 publications

References 40 publications

Nitric oxide metabolism in the human placenta during aberrant maternal inflammation

Nitric oxide metabolism in the human placenta during aberrant maternal inflammation

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways

Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism—Review

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