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)

Iron-derived reactive oxygen species are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic hemolytic anemia, vasculitis, and reperfusion injury. One abundant source of redox active iron is heme, which is inherently dangerous when released from intracellular heme proteins. The present review concerns the involvement of heme in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelium to heme greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of reactive oxygen. Free heme also promotes the conversion of low-density lipoprotein (LDL) into cytotoxic oxidized products. Only because of its abundance, hemoglobin probably represents the most important potential source of heme within the vascular endothelium; hemoglobin in plasma, when oxidized, transfers heme to endothelium and LDL, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defense against such toxicity, upon exposure to heme or hemoglobin, endothelial cells up-regulate heme oxygenase-1 and ferritin. Heme oxygenase-1 is a heme-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide, and the most dangerous product - free redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. Ferritin serves as a protective gene by virtue of antioxidant, antiapoptotic, and antiproliferative actions. These homeostatic adjustments have been shown effective in the protection of endothelium against the damaging effects of exogenous heme and oxidants. The central importance of this protective system was recently highlighted by a child diagnosed with heme oxygenase-1 deficiency, who exhibited extensive endothelial damage.
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PMID:Heme, heme oxygenase and ferritin in vascular endothelial cell injury. 1620 35

The effect of live high-train low on hemoglobin mass (Hbmass) and red cell volume (RCV) in elite endurance athletes is still controversial. We expected that Hb(mass) and RCV would increase, when using a presumably adequate hypoxic dose. An altitude group (AG) of 10 Swiss national team orienteers (5 men and 5 women) lived at 2,500 m (18 h per day) and trained at 1,800 and 1,000 m above sea level for 24 days. Before and after altitude, Hbmass, RCV (carbon monoxide rebreathing method), blood, iron, and performance parameters were determined. Seven Swiss national team cross-country skiers (3 men and 4 women) served as "sea level" (500-1,600 m) control group (CG) for the changes in Hbmass and RCV. The AG increased Hbmass (805+/-209 vs. 848+/-225 g; P<0.01) and RCV (2,353+/-611 vs. 2,470+/-653 ml; P<0.01), whereas there was no change for the CG (Hbmass: 849+/-197 vs. 858+/-205 g; RCV: 2,373+/-536 vs. 2,387+/-551 ml). Serum erythropoietin (P<0.001), reticulocytes (P<0.001), transferrin (P<0.001), soluble transferrin receptor (P<0.05), and hematocrit (P<0.01) increased, whereas ferritin (P<0.05) decreased in the AG. These changes were associated with an increased maximal oxygen uptake (3,515+/-837 vs. 3,660+/-770 ml/min; P<0.05) and improved 5,000-m running times (1,098+/-104 vs. 1,080+/-98 s; P<0.01) from pre- to postaltitude. Living at 2,500 m and training at lower altitudes for 24 days increases Hbmass and RCV. These changes may contribute to enhance performance of elite endurance athletes.
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PMID:Live high-train low for 24 days increases hemoglobin mass and red cell volume in elite endurance athletes. 1649 42

Carbon monoxide, long considered only as a toxic gas, has recently been shown to mediate potent anti-inflammatory and other salutary effects in rodents when it is used at low doses. Carbon monoxide is one of the products of the degradation of heme by heme oxygenase 1. Until recently, these beneficial effects of carbon monoxide were shown only when it was given before a stress stimulus. Hagazi and colleagues have recently shown that this substance is effective even when it is given after a disease process has started. The effects of low doses of carbon monoxide are complemented by the production of biliverdin and probably also by ferritin, which are additional products of heme degradation.
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PMID:Carbon monoxide: from the origin of life to molecular medicine. 1682

The catabolism of heme is carried out by members of the heme oxygenase (HO) family. The products of heme catabolism by HO-1 are ferrous iron, biliverdin (subsequently converted to bilirubin), and carbon monoxide. In addition to its function in the recycling of hemoglobin iron, this microsomal enzyme has been shown to protect cells in various stress models. Implicit in the reports of HO-1 cytoprotection to date are its effects on the cellular handling of heme/iron. However, the limited amount of uncommitted heme in non-erythroid cells brings to question the source of substrate for this enzyme in non-hemolytic circumstances. In the present study, HO-1 was induced by either sodium arsenite (reactive oxygen species producer) or hemin or overexpressed in the murine macrophage-like cell line, RAW 264.7. Both of the inducers elicited an increase in active HO-1; however, only hemin exposure caused an increase in the synthesis rate of the iron storage protein, ferritin. This effect of hemin was the direct result of the liberation of iron from heme by HO. Cells stably overexpressing HO-1, although protected from oxidative stress, did not display elevated basal ferritin synthesis. However, these cells did exhibit an increase in ferritin synthesis, compared with untransfected controls, in response to hemin treatment, suggesting that heme levels, and not HO-1, limit cellular heme catabolism. Our results suggest that the protection of cells from oxidative insult afforded by HO-1 is not due to the catabolism of significant amounts of cellular heme as thought previously.
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PMID:Non-heme induction of heme oxygenase-1 does not alter cellular iron metabolism. 1724 98

The present study aimed to investigate pulmonary function tests (PFTs) in children with thalassemia and to assess the relation between the degree respiratory impairment with the body iron status. High resolution computed tomography of chest (CHRCT) and bronchoalveolar lavage (BAL) was performed to study the cause of pulmonary dysfunction. Thirty-one children with thalassemia over 8 years were included. PFTs were studied including lung volumes and carbon monoxide diffusion capacity (DLco). Patients with abnormal PFTs and/or impaired DLco were further subjected to CHRCT and BAL. Total cell count was measured; differential count was performed on Giemsa and PAP smears. Iron laden macrophages were identified on Perl's stain. PFTs were normal in 51.61%, diffusion capacity impaired in 41.16%, restriction in 16.12%, while obstruction in 3.22% of cases, respectively. There was significant inverse correlation between DLco and serum ferritin. Through multivariate regression analysis, ferritin was found to be a strong predictor for forced vital capacity and total lung capacity. Bronchial dilatation and areas of air trapping were the predominant CHRCT findings. Iron laden macrophages were demonstrated in 14 of 15 patients in BAL. A significant correlation between serum ferritin and DLco, forced vital capacity, total lung capacity, and the presence of iron laden macrophages in BAL indicates that iron plays a major role in the etiopathogenesis of these abnormalities.
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PMID:Study of pulmonary function tests in thalassemic children. 1735 92

Lung function abnormality is a known complication of thalassemia, but the results of studies in pulmonary function have been inconsistent. This study was conducted to describe the type of lung impairment in thalassemic children. Pulmonary function tests were conducted in 40 children with beta-thalassemia major, 23 males and 17 females. Tests included spirometry, total lung capacity (TLC), single breath diffusing capacity of the lung for carbon monoxide (DL(CO)) and arterial blood gases. Serum ferritin level was measured in all children to study its relationship to lung function impairment. A predominantly restrictive pattern was seen in 14 patients (35%). These patients had a significant reduction in RV, FVC, TLC and PEF with an FEV1/FVC ratio of more than 75%. Obstructive airway disease was found in six patients (15%), with an FEV1/FVC ratio less than 75%, increased RV and reduced FEF(25%-75%). Impairment of diffusion was found in 10 patients (25%), with DL(CO) reduced to less than 80% of the predicted value. Arterial blood gases results showed that no patient was hypoxic. No correlation was found between the severity of restrictive or obstructive disease and the serum ferritin level. There was a significant linear correlation between age and serum ferritin level (P < 0.019). Patients with thalassemia have a predominantly restrictive lung dysfunction pattern. This may be due to pulmonary parenchymal pathology, although the reason for the obstructive pattern seen in a small proportion of patients remains obscure.
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PMID:Pulmonary function tests in children with beta-thalassemia major. 1741 49

Iron-derived reactive oxygen species are involved in the pathogenesis of numerous vascular disorders. One abundant source of redox active iron is heme, which is inherently dangerous when it escapes from its physiologic sites. Here, we present a review of the nature of heme-mediated cytotoxicity and of the strategies by which endothelium manages to protect itself from this clear and present danger. Of all sites in the body, the endothelium may be at greatest risk of exposure to heme. Heme greatly potentiates endothelial cell killing mediated by leukocytes and other sources of reactive oxygen. Heme also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. Hemoglobin in plasma, when oxidized, transfers heme to endothelium and lipoprotein, thereby enhancing susceptibility to oxidant-mediated injury. As a defense against such stress, endothelial cells upregulate heme oxygenase-1 and ferritin. Heme oxygenase opens the porphyrin ring, producing biliverdin, carbon monoxide, and a most dangerous product-redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of heme and oxidants; lack of adaptation in an iron-rich environment led to extensive endothelial damage in humans.
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PMID:Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment. 1776 98

Bilirubin is the end product of heme catabolism by heme oxygenases. The inducible form of these enzymes is heme oxygenase-1 (HO-1), which is the rate-limiting enzyme that can degrade heme into equimolar quantities of carbon monoxide (CO), biliverdin, and free iron. Biliverdin is very rapidly converted to bilirubin by the enzyme biliverdin reductase, and free iron upregulates the expression of ferritin. HO-1 is a ubiquitous stress protein and is induced in many cell types by various stimuli. Induced HO-1 exerts antiinflammatory effects and modulates apoptosis. Expression of HO-1 in vivo suppresses the inflammatory responses in endotoxic shock, hyperoxia, acute pleurisy, and organ transplantation, as well as ischemia-reperfusion injury, and thereby provides salutary effects in these conditions. Accumulating evidence indicates that biliverdin/bilirubin can mediate the protective effects of HO-1 in many disease models, such as IRI and organ transplantation, via its antiinflammatory, antiapoptotic, antiproliferative, and antioxidant properties, as well as its effects on the immune response. This review attempts to summarize these protective roles as well as the molecular mechanisms by which biliverdin/bilirubin benefit IRI and solid-organ transplantation, including chronic rejection, and islet transplantation.
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PMID:Therapeutic applications of bilirubin and biliverdin in transplantation. 1791 67

The dissociation of iron from heme is a major factor in iron metabolism and the cellular concentrations of the metal correlate with heme degradation. We tested the hypotheses that (1) exposure to a product of heme catabolism, carbon monoxide (CO), alters iron homeostasis in the lung and in cultured respiratory epithelial cells; (2) this response includes both decreased uptake and increased release of cell metal; and (3) the effects of CO on cell function track changes in metal homeostasis. In rats exposed to 50 ppm CO for 24 hours, non-heme iron concentrations decreased in the lung and increased in the liver. In respiratory epithelial cells cultured at air-liquid interface, CO exposure decreased cell non-heme iron and ferritin concentrations within 2 hours and the effect was fully reversible. CO significantly depressed iron uptake by epithelial cells, despite increased expression of divalent metal transporter-1, while iron release was elevated. The loss of non-heme iron after CO reduced cellular oxidative stress, blocked the release of the proinflammatory mediator (interleukin-8), and interfered with cell cycle protein expression. We conclude that CO reduces the iron content of the lung through both the metal uptake and release mechanisms. This loss of cellular iron after CO is in line with certain biological effects of the gas that have been implicated in the protection of cell viability.
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PMID:Carbon monoxide reversibly alters iron homeostasis and respiratory epithelial cell function. 1820 74

Catabolism of free heme by heme oxygenase-1 (HO-1) generates carbon monoxide, biliverdin, and free iron (Fe). These end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, antiapo-ptotic, antiproliferative, and antioxidant effects. We have identified an additional cytoprotective action, the regulation of complement activation, mediated via induction of decay-accelerating factor (DAF). Pharmacologic inhibition or short-interfering RNA (siRNA) depletion of HO-1 prevented induction of DAF expression in human endothelial cells. In contrast, HO-1 agonists hemin and cobalt protoporphyrin IX significantly increased DAF protein expression, reflecting an increase in transcription and steady-state mRNA. Adenoviral-mediated overexpression of HO-1 increased DAF expression, enhancing protection against C3 deposition and complement-mediated lysis, and this was reversed by DAF inhibitory monoclonal antibody (mAb) 1H4. Likewise, bilirubin, Fe chelation, and overexpression of heavy-chain ferritin all induced DAF expression in endothelial cells (EC). Analysis of cardiac endothelial cells isolated from Hmox1(-/-) mice revealed a 60% reduction in DAF expression compared with Hmox1(+/+) EC, and Hmox1(-/-) cells showed enhanced sensitivity to complement. We propose that modulation of complement activation through induction of DAF represents an important component of the cytoprotective effects of HO-1 against vascular injury, such as that associated with posttransplant vasculopathy, allograft rejection, and ischemia reperfusion.
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PMID:Heme oxygenase-1 expression enhances vascular endothelial resistance to complement-mediated injury through induction of decay-accelerating factor: a role for increased bilirubin and ferritin. 1903


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