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)

Many effector functions of nitrogen monoxide (NO) and carbon monoxide (CO) are mediated through their high-affinity for iron (Fe). In this review, the roles of NO and CO are examined in terms of their effects on the molecular and cellular mechanisms involved in Fe metabolism. Both NO and CO avidly form complexes with a plethora of Fe-containing molecules. The generation of NO and CO is mediated by the nitric oxide synthase and haem oxygenase (HO) families of enzymes respectively. The effects of NO on Fe metabolism have been well characterized, whereas knowledge of the effects of CO remains within its infancy. In terms of the role of NO in Fe metabolism, one of the best characterized interactions includes its effect on the iron regulatory proteins. These molecules are mRNA-binding proteins that control the expression of the transferrin receptor 1 and ferritin, molecules that are involved in Fe uptake and storage respectively. Apart from this, activated macrophages impart their cytotoxic activity by generating NO, which results in marked Fe mobilization from tumour-cell targets. This deprives the cell of the Fe that is required for DNA synthesis and energy production. Considering that HO degrades haem, resulting in the release of CO, Fe(II) and biliverdin, it is suggested that a CO-Fe complex will form. This may account for the rapid Fe mobilization observed from macrophages after haemoglobin catabolism. Intriguingly, overexpression of HO results in cellular Fe mobilization, suggesting that CO has a similar effect to NO on Fe trafficking. Preliminary evidence suggests that, like NO, CO plays important roles in Fe metabolism.
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PMID:Effects of nitrogen monoxide and carbon monoxide on molecular and cellular iron metabolism: mirror-image effector molecules that target iron. 1242 1

The biological significance of the heme oxygenase (HO) system's response to stress reflects functions of its products-CO and bile pigments. CO is a messenger molecule, whereas bile pigments are antioxidants and modulators of cell signaling. Presently, an unexpected mechanism for sustained suprainduction of renal HO-1 following ischemia/reperfusion injury is described. Inhibition of nitric-oxide synthase (NOS) activity by Nomega-nitro-l-arginine methyl ester (l-NAME) at the resumption of reperfusion of rat kidney subjected to bilateral ischemia (30 min) was as effective as the most potent HO-1 inducer, the spin trap agent n-tert-butyl-alpha-phenyl nitrone (PBN), in causing sustained suprainduction of HO-1 mRNA. PBN forms stable radicals of oxygen and nitrogen. Twenty-four hours after reperfusion, HO-1 mRNA measured approximately 30-fold that of the control in the presence of l-NAME treatment; in its absence, the transcript increased to only approximately 5-fold. At 4 h in the presence or absence of the l-NAME HO-1, mRNA was increased by approximately 30-fold. The transcript was translated to active protein as indicated by Western blotting, immunohistochemistry, and activity analyses. l-NAME was not effective given 1 h after resumption of reperfusion. Suprainduction was restricted to the kidney and not detected in the heart and aorta; ferritin expression in the kidney was not effected. It is reasoned that in tissue directly insulted by ischemia/reperfusion, increased production of NO radicals promotes the loss of HO-1 transcript. Because the absence of NO radicals and presence of PBN had a similar effect on HO-1, we propose that suprainduction of the gene is mainly caused by O2 radicals formed on reperfusion. Inhibition of NOS is potentially useful for sustained induction of HO-1 in organs that will be subjected to oxidative-stress insult.
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PMID:Nitric oxide inhibitor N omega -nitro-l-arginine methyl ester potentiates induction of heme oxygenase-1 in kidney ischemia/reperfusion model: a novel mechanism for regulation of the oxygenase. 1267 88

Very little is known about iron metabolism and the mediators of iron metabolism in liver subjected to cold storage before transplantation. Therefore, in this study, we investigated the effect of cold storage on iron homeostasis in the rat liver. When livers were stored at 4 degrees C in University of Wisconsin solution for up to 6 and 24 hours, significant increases occurred in the labile iron pool, ferritin protein, and heme oxygenase activity. Significant decreases in heme content and iron regulatory protein 1 and 2 binding activities occurred by 24 hours. Liver injury indicated by significant increases in University of Wisconsin solution transaminase activity and liver lipid hydroperoxide levels occurred by 6 and 24 hours. Taken together, these results suggest that during pretransplantation cold storage of the liver, an aberrant iron homeostasis develops that contributes to preservation injury, and predisposes the liver to reperfusion injury by iron-dependent reactive oxygen species/Fenton reaction.
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PMID:Deregulation of iron homeostasis and cold-preservation injury to rat liver stored in University of Wisconsin solution. 1268 94

The in vivo effect of hemin on both hepatic oxidative stress and heme oxygenase induction was studied. A marked increase in lipid peroxidation was observed 1 hr after hemin administration. Heme oxygenase-1 activity and expression appeared 6 hr after treatment, reaching a maximum between 12 and 15 hr after hemin administration. Such induction was preceded by a decrease in the soluble and enzymatic defenses, both effects taking place some hours before induction of heme oxygenase. Ferritin content began to increase 6 hr after heme oxygenase induction, and these increases were significantly higher 15 hr after treatment and remained high for at least 24 hr after hemin injection. Co-administration of tin protoporphyrin IX, a potent inhibitor of heme oxygenase, completely prevented the enzyme induction and the increase in ferritin levels, increasing the appearance of oxidative stress parameters. Administration of bilirubin, prevented the heme oxygenase induction as well as the decrease in hepatic GSH and the increase of lipid peroxidation when it was administered 2 hr before hemin treatment. These results indicate that the induction of heme oxygenase by hemin may be a general response to oxidant stress, by increasing bilirubin and ferritin levels and could therefore provide a major cellular defense mechanism against oxidative damage.
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PMID:Bilirubin and ferritin as protectors against hemin-induced oxidative stress in rat liver. 1269 46

Iron-derived reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic haemolytic anaemia, vasculitis and reperfusion injury. One abundant source of redox-active iron is haem, which is inherently dangerous when released from intracellular haem proteins. The present review concerns the likely involvement of haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free haem also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer haem to endothelium, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defence against such toxicity, upon exposure to free haem, endothelial cells up-regulate haem oxygenase-1 and ferritin. Haem oxygenase is a haem-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide and a most dangerous product-free redox-active iron. The latter can be controlled effectively by sequestration within ferritin, a multimeric protein with a very high capacity for storing iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous haem and oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.
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PMID:Haem, haem oxygenase and ferritin in vascular endothelial cell injury. 1281 58

The heme-heme oxygenase system has recently been recognized to possess important regulatory properties. It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection, apoptosis, and inflammation. Heme functions as a double-edged sword. In moderate quantities and bound to protein, it forms an essential element for various biological processes, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. The effect of this free heme on the vascular system is determined by extracellular factors, such as hemoglobin/heme-binding proteins, haptoglobin, albumin, and hemopexin, and intracellular factors, including heme oxygenases and ferritin. Heme oxygenase (HO) enzyme activity results in the degradation of heme and the production of iron, carbon monoxide, and biliverdin. All these heme-degradation products are potentially toxic, but may also provide strong cytoprotection, depending on the generated amounts and the microenvironment. Pre-induction of HO activity has been demonstrated to ameliorate inflammation and mediate potent resistance to oxidative injury. A better understanding of the complex heme-heme
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PMID:Different faces of the heme-heme oxygenase system in inflammation. 1286 63

When cortical neurons are exposed to hemoglobin, they undergo oxidative stress that ultimately results in iron-dependent cell death. Heme oxygenase (HO)-2 is constitutively expressed in neurons and catalyzes heme breakdown. Its role in the cellular response to hemoglobin is unclear. We tested the hypothesis that HO-2 attenuates hemoglobin neurotoxicity by comparing reactive oxygen species (ROS) formation and cell death in wild-type and HO-2 knockout cortical cultures. Consistent with prior observations, hemoglobin increased ROS generation, detected by fluorescence intensity after dihydrorhodamine 123 or dichlorofluorescin-diacetate loading, in wild-type neurons. This fluorescence was significantly attenuated in cultures prepared from HO-2 knockout mice, and cell death as determined by propidium iodide staining was decreased. In other experiments, hemoglobin exposure was continued for 19 h; cell death as quantified by LDH release was decreased in knockout cultures, and was further diminished by treatment with the HO inhibitor tin protoporphyrin IX. In contrast, HO-2 knockout neurons were more vulnerable than wild-type neurons to inorganic iron. HO-1, ferritin, and superoxide dismutase expression in HO-2 -/- cultures did not differ significantly from that observed in HO-2 +/+ cultures; cellular glutathione levels were slightly higher in knockout cultures. These results suggest that heme breakdown by heme oxygenase accelerates the oxidative neurotoxicity of hemoglobin, and may contribute to neuronal injury after CNS hemorrhage.
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PMID:Heme oxygenase-2 knockout neurons are less vulnerable to hemoglobin toxicity. 1455 51

We have investigated heme oxygenase (HO) and antioxidant status in the novel isolation and characterization of aortic endothelial cells (AECs) from a random bred wild-type strain (WILD) and selectively bred atherosclerosis-susceptible (SUS) and -resistant (RES) strains of Japanese quail. Cultured AECs expressed acetylated LDL, and were probed with endothelial and smooth muscle cell specific antibodies to confirm purity of culture. Subconfluent monolayers of RES AECs had higher HO activity than SUS AECs. At confluence, HO activity levels were similar among strains. However, RES AECs had higher HO-1 protein than WILD and SUS cells. Although ferritin protein levels were similar among the three strains, catalytic iron was higher in SUS AECs than WILD and RES cells. Glutathione levels were highest in SUS cells, intermediate in WILD, and lowest in RES, while glutathione reductase was higher in WILD and RES AECs than SUS AECs. We suggest that differences in atherosclerosis susceptibility between RES and SUS may be due, at least in part, to differences in endothelial HO and antioxidant components.
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PMID:Heme oxygenase and antioxidant status in cultured aortic endothelial cells isolated from atherosclerosis-susceptible and -resistant Japanese quail. 1457

Hydroxyacid oxidase 1 (Hao1) is a liver-specific peroxisomal enzyme that oxidizes glycolate to glyoxylate with concomitant production of H2O2. In Hao1 messenger RNA (mRNA), an iron-responsive element (IRE) homologous to the sequence recognized by iron regulatory proteins (IRP), key regulators of iron homeostasis, is present, but the involvement of iron in Hao1 regulation remains unclear. In this study, we found a reduction of Hao1 mRNA content in livers of rats with chronic dietary iron overload, which showed decreased IRP activity and higher ferritin expression as expected, but also induction of heme oxygenase (HO-1), a marker of oxidative damage, and lipid peroxidation. Hao1 mRNA levels were not altered significantly in livers of rats administered doses of iron sufficient to induce ferritin expression and to repress IRP activity, but not to activate HO-1 and to promote lipid peroxidation, as well as in the liver of iron-deficient rats. These observations were not consistent with a post-transcriptional down-regulation of Hao1 by iron through the IRE/IRP pathway and suggested an effect of reactive oxygen species (ROS). Indeed, a marked decrease of Hao1 mRNA was observed in the liver of rats subjected to oxidative stress induced by either glutathione depletion or postischemic reperfusion. Nuclear run-on analysis showed an effect of ROS at the transcriptional level. In conclusion, down-regulation of Hao1 expression during oxidative stress may provide a mechanism to prevent excessive H2O2 formation in liver peroxisomes and may represent the prototype of a poorly recognized but potentially relevant response to oxidative injury involving down-regulation of ROS-producing enzymes.
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PMID:Oxidative stress-mediated down-regulation of rat hydroxyacid oxidase 1, a liver-specific peroxisomal enzyme. 1457 54

Recent studies on cultured aortic endothelial cells (AECs) from atherosclerosis-susceptible (SUS) and -resistant (RES) strains of Japanese quail suggest that differences in atherosclerosis susceptibility between RES and SUS may be due to differences in endothelial heme oxygenase (HO) and antioxidant components. We have now investigated the effects of oxidant-induced injury on HO and glutathione (GSH) in AECs from SUS and RES quail. We report that cultured AECs from SUS and RES birds differ in their response to oxidative stress. AECs from the SUS strain cells are more susceptible than those from the RES strain to oxidative stress induced by tert-butylhydroperoxide, as judged by lower HO activity, HO-1 expression, ferritin and GSH levels. Aortic endothelial cells from SUS birds also showed higher levels of catalytic iron, TBARS production and LDH release compared with RES cells, indicating that SUS AECs are more susceptible to oxidative stress than cells from the resistant strain. Furthermore, independently of genetic status, AECs from old birds have higher TBARS and lower levels of HSP70 induction than AECs from younger birds, suggesting that aging is associated with a decreased ability of AECs to respond to oxidative stress, and this may be relevant to the permissive effect of aging on the process of atherogenesis. Our results indicate that genetic factors and endogenous antioxidant systems in the blood vessel wall may be important in determining the susceptibility of vascular cells to oxidative stress and atherosclerotic plaque formation.
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PMID:Effects of oxidant-induced injury on heme oxygenase and glutathione in cultured aortic endothelial cells from atherosclerosis-susceptible and -resistant Japanese quail. 1467 83


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