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)

The heme biosynthetic and catabolic pathways generate pro- and antioxidant compounds, and consequently, influence cellular sensitivity to oxidants. Heme precursors (delta-aminolevulinic acid, porphyrins) generate reactive oxygen species (ROS), from autoxidation and photochemical reactions, respectively. Heme, an essential iron chelate, serves in respiration, oxygen transport, detoxification, and signal transduction processes. The potential toxicity of heme and hemoproteins points to a critical role for heme degradation in cellular metabolism. The heme oxygenases (HOs) provide this function and participate in cellular defense. This hypothesis emerges from the observation that the activation of HO-1 is an ubiquitous cellular response to oxidative stress. The reaction products of HO activity, biliverdin, and its subsequent metabolite bilirubin, have antioxidant properties. Furthermore, iron released from HO activity stimulates ferritin synthesis, which ultimately provides an iron detoxification mechanism that may account for long-term cytoprotection observed after HO induction. However, such models have overlooked potential pro-oxidant consequences of HO activity. The HO reaction releases iron, which could be involved in deleterious reactions that compete with iron reutilization and sequestration pathways. Indeed, the induction of HO activity may have both pro- and antioxidant sequelae depending on cellular redox potential, and the metabolic fate of the heme iron.
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PMID:The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. 1128 Dec 97

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140+/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0+/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108+/-5 mm Hg and 4.1+/-0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164+/-2 mm Hg) and cardiac hypertrophy (6.9+/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice. Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.
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PMID:Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice. 1137 80

Heme oxygenase-1 (HO-1) is an inducible heat shock protein that regulates heme metabolism to form bilirubin, ferritin and carbon monoxide. Based on recent evidence that HO-1 is involved in the resolution of inflammation by modulating apoptotic cell death or cytokine expression, the present study examined whether overexpression of exogenous HO-1 gene transfer provides a therapeutic effect on a murine model of acute lung injury caused by the type A influenza virus. We demonstrate herein that the transfer of HO-1 cDNA resulted in (1) suppression of both pathological changes and intrapulmonary hemorrhage; (2) enhanced survival of animals; and (3) a decrease of inflammatory cells in the lung. TUNEL analysis revealed that HO-1 gene transfer reduced the number of respiratory epithelial cells with DNA damage, and caspase assay suggested that HO-1 suppressed lung injury via a caspase-8-mediated pathway. These findings suggest the feasibility of HO-1 gene transfer to treat lung injury induced by a pathogen commonly seen in the clinical setting. Since oxidative stress and lung injury are involved in many lung disorders, such as pneumonia induced by a variety of microorganisms and pulmonary fibrosis, HO-1 may be useful for wider clinical applications in gene therapy targeting lung disorders including acute pneumonia and pulmonary fibrosis.
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PMID:Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice. 1159 63

Heme oxygenase-1 (HO-1), a 32-kd microsomal enzyme, is induced as an adaptive response to a wide variety of injurious stimuli. We examined the possible role of HO-1 in cold storage of renal proximal tubular epithelial (RPTE) cells. Hemin, a potent HO-1-inducer, caused a time-dependent increase in HO-1 mRNA and protein expression. Hemin pretreatment of human RPTE cells before cold storage conferred cytoprotection. Increased HO-1 protein was associated with a brisk and early increase in catalytically active iron and a robust increase in cellular ferritin. Deferoxamine, an iron sequestrating antioxidant, prevented hemin-induced iron release and the increase in ferritin, suggesting iron release as an antecedent mechanism for ferritin induction. To verify that the proximate cause of hemin cytoprotection was due to HO-1 induction, we transiently transfected LL-CPK1 porcine kidney cells with a HO-1 expression vector before cold storage. HO-1 transfection resulted in increased expression of HO-1 protein and reduced cell injury during cold storage. The novel observation that prior induction of HO-1 prevents cold storage-induced cell injury suggests that a similar strategy may prove efficacious in preventing cold storage-induced organ damage during transplantation.
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PMID:Overexpression of heme oxygenase protects renal tubular cells against cold storage injury: studies using hemin induction and HO-1 gene transfer. 1170 36

Recent developments in our understanding of the atherosclerotic process and factors that trigger ischemic cardiovascular disease have led to the consideration of antioxidative responses or exogenous antioxidants, which are proposed to inhibit multiple proatherogenic and prothrombotic events in arterial wall. Heme oxygenases (HO), an enzyme essential for heme degradation, have been shown to have such antioxidative properties via the production of bile pigments, carbon monoxide and ferritin induction. We have demonstrated that mildly oxidized LDL markedly induces HO-1, an inducible form of HO, in human aortic endothelial and smooth muscle cell cocultures and that its induction results in the attenuation of monocyte chemotaxis induced by mildly oxidized LDL. We also confirmed abundant expression of HO-1 in human, murine and rabbit atherosclerotic lesions. By modulating HO activities in LDL-receptor knockout mice and Watanabe heritable hyperlipidemic rabbits during their atherosclerotic lesion developments, anti-atherogenic properties of HO have demonstrated as judged by the quantitative analyses of atherosclerotic lesion formation. HO expression was inversely correlated with the levels of plasma and tissue lipid peroxides. HO also influenced on nitric oxide pathway. These observations may suggest that HO, induced during atherosclerotic process, functions as an intrinsic protective pathway in vascular wall.
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PMID:Heme oxygenase as an intrinsic defense system in vascular wall: implication against atherogenesis. 1186 32

Heme oxygenase-1 (HO-1), also known as heat shock protein 32, has been shown to protect against oxidant-induced tissue injury. In the present studies, we analyzed expression of this enzyme in macrophages and hepatocytes following acetaminophen administration and its potential role in hepatotoxicity. Treatment of rats with a hepatotoxic dose of acetaminophen (1 g/kg, ip) resulted in a time-dependent induction of HO-1 in the liver. This was observed within 6 h of acetaminophen administration in both hepatocytes and macrophages. Hepatocytes were found to be more sensitive than macrophages to the effects of acetaminophen on HO-1. Up regulation of HO-1 in the liver following acetaminophen administration correlated with induction of ferritin and manganese superoxide dismutase (MnSOD). To determine if HO-1 was hepatoprotective, rats were pretreated with hemin (30 micromol/kg, ip), a potent inducer of the enzyme. Following hemin treatment, we observed a time-dependent increase in HO-1 protein in the liver and in serum bilirubin levels. Pretreatment of rats with hemin was found to prevent acetaminophen-induced hepatotoxicity, as measured histologically and biochemically by decreased serum transaminase levels. This was correlated with more rapid increases in expression of hepatic ferritin and MnSOD. Heme metabolism via HO-1 generates biliverdin, which is rapidly converted to bilirubin by biliverdin reductase. Pretreatment of rats with biliverdin (40 micromol/kg, ip) was also found to block acetaminophen-induced injury. These data suggest that HO-1 is an important component of antioxidant defense during acetaminophen-induced hepatotoxicity.
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PMID:Differential induction of heme oxygenase-1 in macrophages and hepatocytes during acetaminophen-induced hepatotoxicity in the rat: effects of hemin and biliverdin. 1205 94

Numerous pathologies may involve toxic side effects of free heme and heme-derived iron. Deficiency of the heme-catabolizing enzyme, heme oxygenase-1 (HO-1), in both a human patient and transgenic knockout mice leads to an abundance of circulating heme and damage to vascular endothelium. Although heme can be directly cytotoxic, the present investigations examine the possibility that hemoglobin-derived heme and iron might be indirectly toxic through the generation of oxidized forms of low-density lipoprotein (LDL). In support, hemoglobin in plasma, when oxidized to methemoglobin by oxidants such as leukocyte-derived reactive oxygen, causes oxidative modification of LDL. Heme, released from methemoglobin, catalyzes the oxidation of LDL, which in turn induces endothelial cytolysis primarily caused by lipid hydroperoxides. Exposure of endothelium to sublethal concentrations of this oxidized LDL leads to induction of both HO-1 and ferritin. Similar endothelial cytotoxicity was caused by LDL isolated from plasma of an HO-1-deficient child. Spectral analysis of the child's plasma revealed a substantial oxidation of plasma hemoglobin to methemoglobin. Iron accumulated in the HO-1-deficient child's LDL and several independent assays revealed oxidative modification of the LDL. We conclude that hemoglobin, when oxidized in plasma, can be indirectly cytotoxic through the generation of oxidized LDL by released heme and that, in response, the intracellular defense-HO-1 and ferritin-is induced. These results may be relevant to a variety of disorders-such as renal failure associated with intravascular hemolysis, hemorrhagic injury to the central nervous system, and, perhaps, atherogenesis-in which hemoglobin-derived heme may promote the formation of fatty acid hydroperoxides.
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PMID:Pro-oxidant and cytotoxic effects of circulating heme. 1213 Apr 98

The heme oxygenase-1 (HO-1) system, the rate-limiting step in the conversion of heme, is among the most critical of cytoprotective mechanisms activated during cellular stress. The cytoprotection may result from the elimination of heme and the function of HO-1 downstream mediators, that is, biliverdin, carbon monoxide, and free iron. HO-1 overexpression exerts beneficial effects in a number of transplantation models, including antigen-independent ischemia/reperfusion injury, acute and chronic allograft rejection, and xenotransplantation. The HO-1 system is thought to exert four major functions: (1) antioxidant function; (2) maintenance of microcirculation; (3) modulatory function upon the cell cycle; and (4) anti-inflammatory function. The antioxidant function depends on heme degradation, oxygen consumption, biliverdin, and production of ferritin via iron accumulation. The production of carbon monoxide, which has vasodilation and antiplatelet aggregation properties, maintains tissue microcirculation and may be instrumental in antiapoptotic and cell arrest mechanisms. Heme catabolism and HO-1 overexpression exert profound direct and indirect inhibitory effects on the cascade of host inflammatory responses mediated by neutrophils, macrophages, and lymphocytes. These anti-inflammatory properties result in cytoprotection in a broad spectrum of graft injury experimental models, including ischemia/reperfusion, acute and chronic allograft, and xenotransplant rejection. Further, the multifaceted targets of HO-1-mediated cytoprotection may simultaneously benefit both local graft function and host systemic immune responses. Thus, the HO-1 system serves as a novel therapeutic concept in organ transplantation.
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PMID:Heme oxygenase-1 system in organ transplantation. 1239 29

Heme oxygenase-1 (HO-1) has been found to be a cytoprotective protein, and has recently been identified as a graft survival gene. This study demonstrates that HO-1 expression is increased in human lung allografts with acute cellular rejection and obliterative bronchiolitis. HO-1 expression was correlated with increased tissue iron and/or ferritin expression and increased inflammatory/oxidant load as measured by myeloperoxidase expression. Although the trigger for increased HO-1 expression in this setting is unknown, it may be related to hemorrhage and/or oxidative stress associated with rejection.
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PMID:Increased expression of heme oxygenase-1 in human lung transplantation. 1547 18

Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXalpha, free divalent iron, and carbon monoxide (CO). Among the three isoenzymes cloned to date, only HO-1 can be induced by a variety of seemingly disparate stimuli, most of which are linked by their ability to provoke oxidative stress. Although constitutive expression of HO-1 in the liver is restricted to Kupffer cells, the gene is inducible in nonparenchymal as well as in parenchymal liver cells. HO-1 induction potentially confers protection against oxidative stress in a variety of experimental models, such as liver ischemia/reperfusion secondary to transplantation or hemorrhage/resuscitation. Induction of HO-1 may protect the cell against oxidative injury by (a) controlling intracellular levels of "free" heme (a prooxidant), (b) producing biliverdin (an antioxidant), (c) improving nutritive perfusion via CO release, and (d) fostering the synthesis of the Fe-binding protein ferritin. Although protective effects of up-regulation of the HO pathway--presumably through production of bile pigments and CO--have been reported for a variety of cells and tissues, including the liver, evidence suggests that the protective action might be restricted to a rather narrow threshold of overexpression. High levels of HO-1 may even sensitize the cell to oxidative stress, e.g., through release of reactive iron. Transcriptional activation of the HO-1 gene is an integral part of the cellular response to oxidative stress, but its induction seems to be neither exclusively cytoprotective nor exclusively cytotoxic.
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PMID:Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress. 1247 May 2


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