Use of Iron Chelators in Preventing Hydroxyl Radical Damage: Adult Respiratory Distress Syndrome as an Experimental Model for the Pathophysiology and Treatment of Oxygen-Radical-Mediated Tissue Damage

Marx, Joannes J.M.; Asbeck, B. S. Van

doi:10.1159/000203949

Cited by 43 publications

(17 citation statements)

References 21 publications

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“…In agreement with this notion, the iron chelator, DFO, has been shown to effectively inhibit iron-mediated ROS production in vitro and in vivo (35–37) and protect cells from H 2 O 2 -induced DNA damage (38). Furthermore, DFO can protect against ROS-induced myocardial and coronary endothelial ischemia-reperfusion injury (39, 40) and improve endothelium-dependent vasodilation in CVD patients (41).…”

Section: Discussionmentioning

confidence: 74%

The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice

Zhang

Wu²,

Frei

2010

Exp Biol Med (Maywood)

106

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Objective-Vascular inflammation and monocyte recruitment are initiating events in atherosclerosis that have been suggested to be caused, in part, by iron-mediated oxidative stress and shifts in the intracellular redox environment of vascular cells. Therefore, the objective of this study was to investigate whether the intracellular iron chelator, desferrioxamine (DFO), reduces inflammation and atherosclerosis in experimental mice.Methods and Results-Treatment of C57BL/6J mice with DFO (daily i.p. injection of 100 mg/ kg body weight for two weeks) strongly inhibited lipopolysaccharide-induced increases of soluble cellular adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) in serum and activation of the redox-sensitive transcription factors, nuclear factor κB and activator protein-1, in aorta. Furthermore, treatment of apolipoprotein E-deficient (apoE−/−) mice with DFO (100 mg/ kg, i.p., daily for ten weeks) attenuated aortic atherosclerotic lesion development by 26% (P<0.05). DFO treatment of apoE−/− mice also lowered serum levels of MCP-1 and gene expression of pro-inflammatory and macrophage markers in aorta and heart, in parallel with increased protein expression of the transferrin receptor in the heart and liver. In contrast, DFO treatment had no effect on serum cholesterol and triglyceride levels.Conclusions-These data show that DFO inhibits inflammation and atherosclerosis in experimental mice, providing the proof-of-concept for an important role of iron in atherogenesis. Whether eliminating excess iron is a useful adjunct for the prevention or treatment of atherosclerosis in humans remains to be seen.

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Section: Discussionmentioning

confidence: 74%

The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice

Zhang

Wu²,

Frei

2010

Exp Biol Med (Maywood)

106

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“…Free radicals are highly damaging to organisms (42)(43)(44), and free hydroxyl radicals are one of the most dangerous species (45). Higher organisms have a complicated set of mechanisms to prevent the production of free hydroxyl radicals (46), of which a small component may be the Tyr-Cys cofactor of CDO.…”

Section: Discussionmentioning

confidence: 99%

An Insight into the Mechanism of Human Cysteine Dioxygenase

Ye¹,

Wu²,

Wei³

et al. 2007

Journal of Biological Chemistry

165

134

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Cysteine dioxygenase is a non-heme mononuclear iron metalloenzyme that catalyzes the oxidation of cysteine to cysteine sulfinic acid with addition of molecular dioxygen. This irreversible oxidative catabolism of cysteine initiates several important metabolic pathways related to diverse sulfurate compounds. Cysteine dioxygenase is therefore very important for maintaining the proper hepatic concentration of intracellular free cysteine. Mechanisms for mouse and rat cysteine dioxygenases have recently been reported based on their crystal structures in the absence of substrates, although there is still a lack of direct evidence. Here we report the first crystal structure of human cysteine dioxygenase in complex with its substrate L-cysteine to 2.7 Å , together with enzymatic activity and metal content assays of several single point mutants. Our results provide an insight into a new mechanism of cysteine thiol dioxygenation catalyzed by cysteine dioxygenase, which is tightly associated with a thioether-bonded tyrosine-cysteine cofactor involving Tyr-157 and Cys-93. This cross-linked protein-derived cofactor plays several key roles different from those in galactose oxidase. This report provides a new potential target for therapy of diseases related to human cysteine dioxygenase, including neurodegenerative and autoimmune diseases.Cysteine dioxygenase (CDO, 2 EC 1.13.11.20) is a non-heme mononuclear iron metalloenzyme that catalyzes the irreversible oxidation of cysteine to cysteine sulfinic acid (CSA) with addition of molecular oxygen (1) (Structure 1). This oxidative catabolism of cysteine initiates several important metabolic pathways related to pyruvate and several sulfurate compounds, including sulfate, hypotaurine, and taurine. CDO is expressed at appreciable levels in the brain, kidney, and lung, with extremely high levels in liver tissue (2-5), where CDO plays an important role in maintaining the hepatic concentration of intracellular free cysteine within a proper narrow range (6). When the levels of cysteine decrease below this range, the increase of CDO ubiquitination rate results in rapid degradation of the ubiquitinated portion by the 26 S proteasome system (7,8). However, the precise means by which cysteine regulates CDO ubiquitination remain unknown.Intracellular free cysteine is cytotoxic and neuroexcitotoxic due to oxidative damage via formation of free radicals in the presence of iron (9 -11). Elevated cysteine levels were reported previously in relation to several neurodegenerative diseases, including the well known Parkinson and Alzheimer diseases (12-14), and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (15, 16). CDO is considered to be involved in these diseases due to its function in regulating free cysteine levels.Sequence alignment classifies CDO as a member of the cupin superfamily (see Fig. 1), whose members possess what may be the most diverse range of functions, encompassing ϳ18 subclasses. Nonetheless, neither of the exact characteristic conserved sequenc...

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“…53 Reactive oxygen species, possibly formed through iron-catalyzed Fenton reaction, may be involved in atherogenesis. In our study, DMTU inhibited iron-induced monocyte adherence to HUVECs.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Labile Iron Modulates Adhesion of Human Monocytes to Human Endothelial Cells

Kartikasari

Georgiou

Visseren

et al. 2004

ATVB

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Objective-Elevated iron stores and high plasma iron concentration have been linked to an increased risk of atherosclerosis.Iron may thereby affect the interaction of monocytes to endothelium, an initial event in the formation of atherosclerotic plaques. Methods and Results-Addition of 10 mol/L non-transferrin-bound iron to the incubation medium caused a 2-fold increase in monocyte adhesion to human umbilical vein endothelial cells (HUVECs). A concordant increase in the expression of the following adhesion molecules was observed: vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and endothelial selectin on HUVECs as well as very late antigen-4, and lymphocyte function-associated antigen-1 on monocytes. The inclusion of either deferiprone or salicylaldehyde isonicotinoylhydrazone counteracted these effects. Intracellular iron chelation by deferoxamine was completed only after 10 hours of incubation, shown by reversal of iron-quenched intracellular calcein signal, and concurrently the effects of iron were blunted. The membrane-impermeable chelator, diethylenetriamine pentaaceticacid, failed to negate iron effects, even after 48 hours of treatment. Furthermore, only membrane-permeable superoxide or hydroxyl radical scavengers were capable of preventing HUVEC activation by iron. Conclusions-Non-transferrin-bound iron increases the level of intracellular labile iron, which promotes monocyte recruitment to endothelium and may thereby contribute to the pathogenesis of atherosclerosis. Iron-induced adhesion molecule expression was observed, and this event may involve the production of oxygen radicals. Key Words: iron Ⅲ atherosclerosis Ⅲ monocytes Ⅲ endothelium Ⅲ adhesion molecules A therosclerosis has been associated with several important environmental and genetic risk factors. It is characterized by inflammatory changes leading to plaque formation and, furthermore, to plaque rupture and arterial thrombosis. Transendothelial migration of leukocytes is a fundamental inflammatory mechanism in atherogenesis. 1 This process is partly mediated by the interaction between endothelial adhesion molecules and their ligands on monocytes.Elevated concentrations of adhesion molecules have been observed in human atherosclerotic plaques, including 2 members of the immunoglobulin superfamily of adhesion receptors, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as a member of the selectin family, endothelial selectin (E-Selectin). Moreover, a significant correlation has been found between the degree of macrophage infiltration and endothelial ICAM-1, VCAM-1, and E-selectin expression in atherosclerotic lesions. 2 The infiltration of leukocytes consists of consecutive adhesion-mediated events. The first step of adhesion involves binding of selectins to carbohydrate ligands that triggers tethering of the leukocytes to the activated endothelium along the vessel wall. Arrest and firm adhesion of the leukocytes on activated endothelial cells occur depending on the activat...

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Use of Iron Chelators in Preventing Hydroxyl Radical Damage: Adult Respiratory Distress Syndrome as an Experimental Model for the Pathophysiology and Treatment of Oxygen-Radical-Mediated Tissue Damage

Cited by 43 publications

References 21 publications

The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice

The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice

An Insight into the Mechanism of Human Cysteine Dioxygenase

Intracellular Labile Iron Modulates Adhesion of Human Monocytes to Human Endothelial Cells

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