Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrogen monoxide (NO) is a cytotoxic effector molecule produced by macrophages that results in Fe mobilization from tumour target cells which inhibits DNA synthesis and mitochondrial respiration. It is well known that NO has a high affinity for Fe, and we showed that NO-mediated Fe mobilization is markedly potentiated by glutathione (GSH) generated by the hexose monophosphate shunt [Watts, R.N. & Richardson, D.R. (2001) J. Biol. Chem. 276, 4724-4732]. We hypothesized that GSH completes the coordination shell of an NO[bond]Fe complex that is released from the cell. In this report we have extended our studies to further characterize the mechanism of NO-mediated Fe mobilization. Native PAGE 59Fe-autoradiography shows that NO decreased ferritin-59Fe levels in cells prelabelled with [59Fe]transferrin. In prelabelled cells, ferritin-59Fe levels increased 3.5-fold when cells were reincubated with control media between 30 and 240 min. In contrast, when cells were reincubated with NO, ferritin-59Fe levels decreased 10-fold compared with control cells after a 240-min reincubation. However, NO could not remove Fe from ferritin in cell lysates. Our data suggest that NO intercepts 59Fe on route to ferritin, and indirectly facilitates removal of 59Fe from the protein. Studies using the GSH-depleting agent, L-buthionine-(S,R)-sulphoximine, indicated that the reduction in ferritin-59Fe levels via NO was GSH-dependent. Competition experiments with NO and permeable chelators demonstrated that both bind a similar Fe pool. We suggest that NO requires cellular metabolism in order to effect Fe mobilization and this does not occur via passive diffusion down a concentration gradient. Based on our results, we propose a model of glucose-dependent NO-mediated Fe mobilization.
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PMID:The mechanism of nitrogen monoxide (NO)-mediated iron mobilization from cells. NO intercepts iron before incorporation into ferritin and indirectly mobilizes iron from ferritin in a glutathione-dependent manner. 1213 76

To investigate the changes in nitric oxide (NO) production during and after normal pregnancy and in pregnancies complicated by preeclampsia, we measured serum nitrates and nitrites (NOx) concentrations and serum iron markers in 347 subjects. Serum NOx concentrations were determined after reduction of nitrates to nitrites using the Griess reaction. Serum iron and serum ferritin were assayed using an automatic chemical analyzer and a chemiluminescence method. Serum NOx concentrations were significantly higher in the first trimester (117.3 +/- 31.4 microM) than in nonpregnant women (23.8 +/- 7.1 microM). High NOx concentrations persisted throughout normal pregnancy, irrespective of serum ferritin concentrations, and returned to nonpregnant levels by 9-12 wk postpartum. Mean NOx concentrations in preeclamptic women were 43.1 +/- 12.7 microM, which were significantly lower than those in the gestation age-matched normal pregnant women (249.7 +/- 51.3 microM). In summary, NO production increases with advancing gestation during normal pregnancy and decreases in preeclampsia, regardless of serum ferritin concentrations. Elevated NOx concentrations during pregnancy return to normal within 12 wk after delivery.
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PMID:Nitric oxide production increases during normal pregnancy and decreases in preeclampsia. 1217 88

Iron regulatory proteins (IRP1 and IRP2) control the synthesis of transferrin receptors (TfR) and ferritin by binding to iron-responsive elements (IREs) that are located in the 3' untranslated region (UTR) and the 5' UTR of their respective mRNAs. Cellular iron levels affect binding of IRPs to IREs and consequently expression of TfR and ferritin. Moreover, NO(.), a redox species of nitric oxide that interacts primarily with iron, can activate IRP1 RNA-binding activity resulting in an increase in TfR mRNA levels and a decrease in ferritin synthesis. We have shown that treatment of RAW 264.7 cells (a murine macrophage cell line) with NO(+) (nitrosonium ion, which causes S-nitrosylation of thiol groups) resulted in a rapid decrease in RNA-binding of IRP2, followed by IRP2 degradation, and these changes were associated with a decrease in TfR mRNA levels and a dramatic increase in ferritin synthesis. Moreover, we demonstrated that stimulation of RAW 264.7 cells with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) increased IRP1 binding activity, whereas RNA-binding of IRP2 decreased and was followed by a degradation of this protein. Furthermore, the decrease of IRP2 binding/protein levels was associated with a decrease in TfR mRNA levels and an increase in ferritin synthesis in LPS/IFN-gamma-treated cells, and these changes were prevented by inhibitors of inducible nitric oxide synthase. These results suggest that NO(+)-mediated degradation of IRP2 plays a major role in iron metabolism during inflammation.
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PMID:Nitric oxide-mediated modulation of iron regulatory proteins: implication for cellular iron homeostasis. 1254 30

Iron regulatory proteins (IRP1 and IRP2) control the synthesis of transferrin receptors (TfR) and ferritin by binding to iron-responsive elements (IREs) which are located in the 3' untranslated region (UTR) and the 5' UTR of their respective mRNAs. Cellular iron levels affect binding of IRPs to IREs and consequently expression of TfR and ferritin. Moreover, NO*, a redox species of nitric oxide that interacts primarily with iron, can activate IRP1 RNA-binding activity resulting in an increase in TfR mRNA levels. We have shown that treatment of RAW 264.7 cells (a murine macrophage cell line) with NO+ (nitrosonium ion, which causes S-nitrosylation of thiol groups) resulted in a rapid decrease in RNA-binding of IRP2, followed by IRP2 degradation, and these changes were associated with a decrease in TfR mRNA levels. Moreover, we demonstrated that stimulation of RAW 264.7 cells with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) increased IRP1 binding activity, whereas RNA-binding of IRP2 decreased and was followed by a degradation of this protein. Furthermore, the decrease of IRP2 binding/protein levels was associated with a decrease in TfR mRNA levels in LPS/IFN-gamma-treated cells, and these changes were prevented by inhibitors of inducible nitric oxide synthase. These results suggest that NO+-mediated degradation of IRP2 plays a major role in iron metabolism during inflammation.
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PMID:Role of nitric oxide in cellular iron metabolism. 1257 72

The iron regulatory proteins (IRPs) are an example of different proteins regulating the same metabolic process, iron uptake and metabolism. IRP1 is an iron-sulfur cluster-containing protein that can be converted from a cytosolic aconitase to an RNA binding posttranscriptional regulator in response to nitric oxide (NO). IRP2 lacks aconitase activity and its expression is decreased by NO signaling. In macrophages, NO is produced in response to such inflammatory ligands as interferon-gamma, which is expressed in response to mitogenic and antigenic stimuli, and lipopolysaccharide, a marker of bacterial invasion. Until recently, research results predict that the cellular response to increased NO production should be a decrease in ferritin synthesis, due to IRP1 binding to ferritin mRNA, and an increase in transferrin receptor biosynthesis, due to IRP1 binding to the transferrin mRNA. Surprisingly, however, macrophages exhibit decreased transferrin receptor concentration in response to inflammatory ligands. Bouton and Drapier discuss the physiological role and the mechanisms that may underlie this contradictory response.
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PMID:Iron regulatory proteins as NO signal transducers. 1274 46

Concentrations of ferritin in alveolar cells and on the alveolar surface are increased in patients with a variety of respiratory disorders. Ferritin synthesis by cells is modulated by iron content but is also influenced by stimuli other than iron. In this study we sought to determine whether in vitro exposure to hypoxia- or nitric oxide (NO)-induced ferritin accumulation or release by human alveolar macrophages (AMs) or a lung cancer-derived epithelial cell line (A549). Changes in cell content of iron and ferritin (L- and H-types), as well as ferritin content of cell supernatants, were determined after in vitro exposure to hypoxia (1% or 10% O(2), 18 hours) or the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 0.01-1.0 mmol/L, 18 hours). Exposure to 1% O(2) increased ferritin content in both cell types (>fourfold increase; P <.005) without changing iron content. Treatment with SNAP increased ferritin content of A549 cells in a dose-dependent manner, whereas treatment of AMs decreased cellular iron and ferritin content and increased supernate ferritin content. Pretreatment of cells with N-acetylcysteine (500 micromol/L) reduced hypoxia-induced ferritin accumulation in alveolar cells and completely inhibited NO-induced ferritin accumulation in A549 cells. These findings indicate that exposure to 1% O(2)can increase ferritin content in alveolar cells, whereas NO can increase ferritin content (A549 cells) or decrease ferritin content (AMs).
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PMID:Effects of hypoxia and nitric oxide on ferritin content of alveolar cells. 1276 71

To explore the role of nitric oxide (NO) in the pathogenesis and effect on regulation of iron metabolism in anemia of chronic disease (ACD) and provide experimental evidence for prevention and treatment of ACD. On the basis of traditional animal model of rheumatoid arthritis, an ACD rat model was established by repeated injection of Freund's complete adjuvant. The relationship between NO concentration and iron metabolism was observed in ACD rats with and without NO synthase inhibitor, L-NAME, (N omega-nitro-L-arginine methyl ester L-NAME). The results showed that anemia was induced in the rat model. In the ACD group, NO concentration and NO synthase activity in serum increased; iron, total iron binding capacity (TIBC) and transferrin saturation (TS) in serum and ferritin in erythrocytes (rFn) decreased; transferrin receptor (TfR) and iron in bone marrow cells decreased; ferritin in serum and iron in liver increased and meanwhile the acotinase activity in liver decreased. After administration of L-NAME, anemia was improved, when NO, NO-synthase activity, liver iron and serum ferritin decreased, but serum iron, TS, TIBC, rFn, TfR, iron in marrow cells and liver acotinase activity elevated. The levels of parameters for iron metabolism in ACD + L-NAME group were situated between ACD and control groups. It is concluded that NO plays an important role in pathogenesis of ACD and influences the regulation of iron in ACD. Decrease of NO level as early as possible will benefit to block the development of anemia, that will provide a new strategy of therapy for ACD.
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PMID:[Effect of nitric oxide on iron metabolism in rats with anemia of chronic disease]. 1296 68

Heme oxygenase (HO), an enzyme essential for heme degradation, shows anti-oxidative and anti-inflammatory properties via the production of bile pigments, carbon monoxide (CO) and ferritin induction under various pathophysiological conditions. A number of recent studies have shown biological effects of HO reaction in cardiovascular disorders. An inducible form of HO, HO-1, is induced by a variety of stresses such as oxidized lipoproteins, cytokines, hemodynamic changes, angiotensin II and nitric oxide (NO) in vascular wall. HO-1 induction seems to function as an adaptive response against these injurious stimuli. HO-1 induction in artery wall scavenges reactive oxygen species, which leads to the attenuation of monocyte adhesion and chemotaxis. HO-1 induction also reduces lipid peroxidation in plasma and artery wall. These properties of HO-1 suggest anti-atherogenic roles of this enzyme. In this review, roles of endothelial HO-1 expression and bilirubin in atherogenesis are also discussed. HO-1 also seems to play a significant role in restenosis after angioplasty, which is a major clinical problem associated with atherosclerosis. Recent progress in human HO-1 genetics supports these experimental results. This review aims to reaffirm current problems in the biological aspects of HO and suggest future research direction and clinical application.
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PMID:Heme oxygenase-1 against vascular insufficiency: roles of atherosclerotic disorders. 1452 48

Heme oxygenase-1 (HO-1) is part of the integrated response to oxidative stress. This enzyme may exert anti-inflammatory effects in some animal models, although the precise mechanisms are not fully understood. We have examined the role of HO-1 in the inflammatory response induced by zymosan in the mouse air pouch. Zymosan administration induced HO-1 protein expression in leukocytes migrating to exudates, with maximal levels in the late phase of this response (24-48 h). This was accompanied by ferritin induction and bilirubin accumulation, indicating that this enzyme is active in our model. HO-1 expression by zymosan treatment was partly reduced by aminoguanidine, suggesting the participation of endogenous nitric oxide in the mechanisms leading to HO-1 synthesis in the zymosan-injected mouse air pouch. Up-regulation of HO-1 by hemin administration resulted in inhibition of nitric-oxide synthase-2 activity, cellular infiltration into the air pouch exudate, and plasmatic exudation. Leukotriene B4 levels in exudates were significantly decreased in the early phase of this response (4 h), whereas interleukin-1beta and tumor necrosis factor-alpha were inhibited at all time points. Inhibition of HO-1 activity by zinc protoporphyrin IX prevented most of the effects caused by hemin administration. Our results indicate that HO-1 exerts anti-inflammatory effects on the response to zymosan in the mouse air pouch and support a role for this enzyme in the modulation of inflammatory processes.
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PMID:Beneficial effects of heme oxygenase-1 up-regulation in the development of experimental inflammation induced by zymosan. 1456 52

Nitric acid esters such as glyceryl trinitrate were introduced into therapy more than a century ago and are still widely used for the treatment of myocardial ischemia and its main symptom angina pectoris. The basic mechanisms responsible for the vasodilatory and anti-ischemic action of organic nitrates involve bioactivation of, and nitric oxide (NO) release from, these compounds which have therefore been termed NO donors. The organic nitrate pentaerythritol tetranitrate (PETN) is known to possess antioxidant properties that are thought to be the underlying cause for its specific pharmacological profile. In contrast to other long-acting nitrates, PETN induces tolerance- free vasodilation in humans and was reported to prevent endothelial dysfunction as well as atherogenesis in cholesterol- fed rabbits. However, the exact nature of the vasoprotective signaling pathways triggered by PETN has remained obscure. The present study demonstrates that the active PETN metabolite PETriN stimulates protein expression of the antioxidant defense protein heme oxygenase-1 (HO-1; Figures 1 and 2). Additionally, PETriN enhanced the enzymatic activity of HO-1 measured as formation of the HO-1 metabolites bilirubin (Figure 3) and carbon monoxide (Figure 4) in lysates from endothelial cells. HO-1 induction subsequently led to a marked increase in protein expression of a second antioxidant protein, ferritin, via the HO-1-dependent release of free iron from endogenous heme sources (Figures 1 and 5). Pretreatment of endothelial cells with PETriN was followed by increased cellular resistance to oxidant injury mediated by hydrogen peroxide (Figure 6). Endothelial protection by PETriN was mimicked by exogenous bilirubin which led to an almost complete reversal of hydrogen peroxide-induced toxicity (Figure 8). Increased HO-1 and ferritin expression as well as endothelial protection occurred at micromolar concentrations of PETriN which are well within the range of plasma or tissue levels that can be expected during oral therapy. The capacity to protect the endothelium in vitro may translate into and explain the previously observed antiatherogenic actions of PETN in vivo. In this study, another long-acting nitrate, isosorbide dinitrate (ISDN), did not protect endothelial cells from oxidant damage (Figure 6). The absence of significant cytoprotection in the presence of ISDN was paralleled by a lack of HO-1 and ferritin stimulatory capacity (Figures 2 and 5). ISDN had no significant effect on carbon monoxide release or bilirubin formation (Figures 3 and 4). These observations are in agreement with results demonstrating small or nondetectable amounts of NO released from ISDN and its active metabolite isosorbide mononitrate (ISMN) measured as cyclic GMP formation in RFL-6 reporter cells (Figure 7). Interestingly and in contrast to PETN, isosorbide nitrates are known to induce tolerance to their cardiovascular effects, presumably via oxidant stress. Moreover, in earlier investigations aimed at assessing the antiatherogenic potential of nitrates, PETN but not isosorbide nitrates prevented plaque formation and endothelial dysfunction in animal models of atherosclerosis. Thus, the ability to activate HO-1 induction and associated antioxidant pathways apparently distinguishes PETN from other long-acting nitrates and may explain their different patterns of action in vivo (Figure 9).
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PMID:[Therapy with NO donors-antiatherogenic and antioxidant actions]. 1496 47


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