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)

Heme oxygenase (HO) proteins are members of the HSP30 family and consist of 2 isozymes identified to date, termed HO-1 and HO-2. Separate genes encode the isozymes and protein products which are immunochemically distinct, share less than 50% similarity at the amino acid sequence level. Each form, however, shows greater than 90% similarity among species, including human and the rat (reviewed in ref.). Furthermore, these isozymes function in a well-defined role to carry out oxidation of the heme molecule (Fe-protoporphyrin IX) in concert with NADPH-cytochrome P450 reductase. The oxidation of heme is isomer specific and results in the formation of bile pigments, carbon monoxide, and iron. The heme molecule constitutes the prosthetic moiety of hemoproteins, such as hemoglobin, myoglobin, catalase, soluble guanylate cyclase, cytochrome b5, cytochromes P450 and NO synthase. HO-1 also known as heat shock protein (HSP) 32 is encoded by a gene which is exquisitely stress-responsive and a host of stimuli that mediate oxidative stress cause induction of the protein both in vivo and in vitro. The HO-2 form shows a unique pattern of regulation from that of HO-1. HO-2 is a constitutive protein and its expression is not affected by the inducers of HO-1 tested to date; rather, the only known regulator of HO-2 yet identified is adrenal glucocorticoids. The two isozymes display vast differences in tissue distribution and under normal conditions HO-1 is present in the whole brain at the limit of immunodetection and is discreetly localized in select neuronal populations. HO-1 protein (approximately 32 kDa) and its approximately 1.8 kb transcript are increased, however, in response to stressful stimuli primarily in non-neuronal cell populations. The heme oxygenase system serves in both a catabolic and anabolic capacity in the cell. In the former capacity, it down-regulates cellular heme and hemoprotein levels. And, as such it inactivates the most effective catalyst for formation of free radicals, the heme molecule. In its anabolic role, as noted above, heme oxygenase produces bile pigments, carbon monoxide, and iron, all of which are biologically active: bile pigments function as antioxidants; the carbon monoxide generated by HO activity has been correlated with the generation of cGMP; and iron regulates expression of various genes, including that of HO-1 itself, as well as transferrin receptors, ferritin, and NO synthase. We used rabbit anti-rat HO-2 polyclonal antibody and HO-2 cDNA to localize HO-2 immunoreactive protein and the 1.3- and 1.9 kb homologous transcripts, respectively, in rodent brain as visualized by histochemical staining procedures. These protocols provide the first detailed description of methodologies successfully used to define the pattern of HO-2 expression at the transcriptional and translational levels in the adult rat brain and glucocorticoid-treated newborn rats. The procedures described herein have the virtue of being non-radioactive, as well as applicability to the systemic organs, such as the cardiovascular system and the male reproductive organs. Visualization of cellular HO-2 expression aids in assessment of potential sites of carbon monoxide, iron, and bilirubin production within the nervous system.
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PMID:Histochemical localization of heme oxygenase-2 protein and mRNA expression in rat brain. 938 81

Heme oxygenase-1 (HO-1, HSP32) is an early gene that is responsive to an array of pathological conditions including, but not limited to, hypoxia and cerebral ischemia. HO-1 cleaves the heme molecule and produces carbon monoxide (CO) and biliverdin (an antioxidant) and is essential for iron homeostasis. The purpose of this study was to investigate, using transgenic (Tg) mice, whether overexpression of HO-1 in the brain augments or attenuates cellular injury caused by ischemic stroke. Homozygous HO-1 Tg mice that overexpress HO-1 under the control of the neuron-specific enolase promoter (characterized previously) were used. Under halothane anesthesia and normothermic conditions, wild-type nontransgenic (nTg; n = 22) and HO-1 Tg (n = 24) mice were subjected to middle cerebral artery occlusion (MCAo). Six hours after induction of ischemia, Tg and nTg mice developed infarcts that were 39 +/- 6 and 63 +/- 9 mm3, respectively (p < 0.01). No significant difference between the two strains was observed in the values of brain edema (11.3 +/- 4% in Tg vs. 14.6 +/- 5% in nTg; p < 0.1). At 24 h after MCAo, Tg mice exhibited significant neuroprotection as determined by the stroke volumes (41 +/- 2 mm3 in Tg vs. 74 +/- 5 mm3 in nTg; p < 0.01) and values of ischemic cerebral edema (21 +/- 6% in Tg vs. 35 +/- 11% in nTg; p < 0.01). Data suggest that neuroprotection in Tg mice was, at least in part, related to the following findings: (a) constitutively up-regulated cyclic GMP and bcl-2 levels in neurons; (b) inhibition of nuclear localization of p53 protein; and (c) antioxidant action of HO-1, as detected by postischemic neuronal expression of ferritin, and decreases in iron staining and tissue lipid peroxidation. We suggest that pharmacological stimulation of HO-1 activity may constitute a novel therapeutic approach in the amelioration of ischemic injury during the acute period of stroke.
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PMID:Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. 1003 92

The organic nitrate pentaerithrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In porcine aortic endothelial cells, a 24 h incubation with PETN (1-100 microM) or its metabolite pentaerithrityl trinitrate (PETriN) increased levels of the antioxidant protein ferritin up to three-fold over basal, whereas isosorbide dinitrate and isosorbide-5-mononitrate were without significant effect under these conditions. PETriN-induced ferritin expression was blocked by the NO scavenger PTIO but remained unaltered in the presence of ODQ, an inhibitor of soluble guanylyl cyclase. 8-Bromo cyclic GMP and dibutyryl cyclic GMP did not influence basal ferritin synthesis. The iron chelator desferrioxamine abolished ferritin induction by PETriN. Our results show that PETN or its active metabolite PETriN induce ferritin synthesis through NO- and iron-dependent but cyclic GMP-independent pathways. Increased activity of ferritin may contribute to, and at least in part explain, the specific antiatherogenic and antioxidant action of PETN.
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PMID:The antioxidant defense protein ferritin is a novel and specific target for pentaerithrityl tetranitrate in endothelial cells. 1040 18

Amino acid sequences of ferritin subunits from three orders of insects (Diptera: Drosophila and Aedes; Lepidoptera: Calpodes and Manduca; and Homoptera: Nilaparvata) were obtained from the public database, and analyzed using structural modeling algorithms. Pattern recognition analysis identifies cell attachment, glycosylation, myristoylation, microbody targeting, phosphorylation, cAMP/cGMP dependent, protein kinase C, casein kinase, and tyrosine kinase sites in these subunits. The modeling analyses suggest that the insect heavy-chain homologues are similar to their vertebrate analogues and retain all active sites, including the ferroxidase center. On the contrary, the insect light-chain homologues are different from their vertebrate counterparts, and show none of these features. Five alpha-helices were located in the Dipteran and Lepidopteran, but not in Homopteran ferritin subunits.
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PMID:Molecular modeling of insect ferritins. 1180 75

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

Differential screening of a Littorina littorea (the common periwinkle) cDNA library identified ferritin heavy chain as an anoxia-induced gene in hepatopancreas. Northern blots showed that ferritin heavy chain transcript levels were elevated twofold during anoxia exposure, although nuclear run-off assays demonstrated that ferritin heavy chain mRNAs were not transcriptionally upregulated during anoxia. Polysome analysis indicated that existing ferritin transcripts were actively translated during the anoxic period. This result was confirmed via western blotting, which demonstrated a twofold increase in ferritin heavy chain protein levels during anoxia, with a subsequent decrease to control levels during normoxic recovery. Organ culture experiments using hepatopancreas slices demonstrated a >50% increase in ferritin heavy chain transcript levels in vitro under conditions of anoxia and freezing, as well as after incubation with the second messenger cGMP. Taken together, these results suggest that ferritin heavy chain is actively regulated during anoxia exposure in the marine snail, L. littorea.
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PMID:Accumulation and translation of ferritin heavy chain transcripts following anoxia exposure in a marine invertebrate. 1501 Apr 86

Heme oxygenase (HO) degrades heme to carbon monoxide (CO), ferrous ions, and the bile pigment biliverdin, which is subsequently reduced to the other important bile pigment, bilirubin, by biliverdin reductase. Fe2+ liberated from the heme molecule upregulates ferritin production, and bile pigments are potent endogenous antioxidants. The HO enzyme exists in three isophorms: HO-1 is expressed at low levels under physiological conditions, but is induced by numerous factors, including oxidative stress, inflammation, nitric oxide, an elevated level of substrate, and hypoxia. HO-2 is a constitutive enzyme involved in the baseline production of CO in the cardiovascular and nervous systems, whereas HO-3 is also ubiquitously expressed, but possesses low catalytic activity. Like nitric oxide, CO activates soluble guanylate cyclase and elevates cGMP in target tissues, which dilates blood vessels. It also does this by directly activating potassium channels in vascular smooth muscle cells. In addition, CO inhibits platelet aggregation and proliferation of vascular smooth muscle cells, inhibits apoptosis, and stimulates angiogenesis. Both deficiency, and excess of HO-1 may be involved in the pathogenesis of arterial hypertension. Induction of HO-1 attenuates atherosclerosis and myocardial ischemia-reperfusion injury. Pharmacological and genetic induction of HO-1 as well as the delivery of exogenous CO are promising therapeutic strategies for the treatment of cardiovascular diseases.
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PMID:[Heme oxygenase and carbon monoxide in the physiology and pathology of the cardiovascular system]. 1506 78

Atrial natriuretic peptide (ANP)-preconditioned livers are protected from ischemia-reperfusion injury. ANP-treated organs show increased expression of heme oxygenase (HO)-1. Because HO-1 liberates bound iron, the aim of our study was to determine whether ANP affects iron regulatory protein (IRP) activity and, thus, the levels of ferritin. Rat livers were perfused with Krebs-Henseleit buffer [+/-ANP, 8-bromo-cGMP (8-Br-cGMP), and tin protoporphyrin, 20 min], stored in University of Wisconsin solution (4 degrees C, 24 h), and reperfused (120 min). IRP activity was assessed by gel-shift assays, and ferritin, IRP phosphorylation, and PKC localization were assessed by Western blot. Control livers displayed decreased IRP activity at the end of ischemia but no change in ferritin content during ischemia and reperfusion. ANP-pretreated livers showed reduced IRP activity, an effect mimicked by 8-Br-cGMP. Ferritin levels were increased in ANP-pretreated organs. Simultaneous perfusion of livers with ANP and tin protoporphyrin did not reduce ANP-induced action, arguing against a role for HO-1 in changes in IRP activity. ANP and 8-Br-cGMP decreased membrane localization of PKC-alpha and PKC-epsilon, but this modulation of PKC seems unrelated to inhibition of IRP binding. This work shows the cGMP-mediated attenuation of IRP binding activity by ANP, which results in increased hepatic ferritin levels. This change in IRPs is independent of ANP-induced HO-1 and reduced PKC activation.
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PMID:ANP-induced decrease of iron regulatory protein activity is independent of HO-1 induction. 1508 80

Emerging evidence indicates that aldosterone causes oxidative stress by stimulating proinflammatory/oxidative mediators, including nuclear factor-kappaB, activating protein (AP-1), and c-Jun N-terminal kinase. Thus, in insulin-resistant type 2 diabetes (T2D), oxidative stress generated by hyperglycemia and aldosterone would potentiate the oxidative destruction of tissue and important regulators of glucose metabolism like adiponectin and insulin. Although heme oxygenase (HO)-1 is cytoprotective, its effects on T2D have not been fully characterized. Here we report an enduring antidiabetic effect of the HO inducer, hemin, on Zucker diabetic-fatty rat (ZDF), a model of insulin-resistant T2D. Chronically applied hemin to ZDF reduced and maintained significantly low fasting and postprandial hyperglycemia for 4 months after therapy. The antidiabetic effect was accompanied by enhanced HO activity, catalase, cyclic GMP, bilirubin, ferritin, total antioxidant capacity, and insulin. In contrast, reduced aldosterone alongside markers/mediators of oxidative stress, including 8-isoprostane, c-Jun N-terminal kinase, nuclear factor-kappaB, AP-1, and AP-2 were observed. Interestingly, in hemin-treated ZDF, inhibitory proteins of insulin-signaling, such as glycogen synthase kinase-3 and protein-tyrosine phosphatase-1B were reduced, whereas agents that promote insulin signaling including adiponectin, cAMP, AMP-activated protein kinase, aldolase-B, and glucose transporter-4 (GLUT4), were robustly increased. Correspondingly, hemin improved ip glucose tolerance, reduced insulin intolerance, and lowered insulin resistance (homeostasis model assessment of insulin resistance), and the inability of insulin to enhance GLUT4 was overturned. These results suggest that the suppression of hyperglycemia and aldosterone-induced oxidative stress alongside the potentiation of insulin-sensitizing pathways may account for the 4-month enduring antidiabetic effect. The synergistic interaction between the HO system, aldolase-B, adiponectin, AMP-activated protein kinase, and GLUT4 may be explored for novel strategies against postprandial/fasting hyperglycemia and insulin-resistant T2D.
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PMID:The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways. 1910 28

Upregulating the heme oxygenase (HO) system removes the prooxidant heme, and thus is cytoprotective. Additionally, the products from the HO pathway including, carbon monoxide, bilirubin, and biliverdin, scavenge reactive oxygen species, inhibit lipid peroxidation, and suppress tissue inflammation, while the iron formed enhances the synthesis of the antioxidant ferritin. Deoxycorticosterone acetate (DOCA)-salt hypertension, a model of human primary aldosteronism, causes oxidative stress and impairs renal function by stimulating inflammatory/oxidative transcription factors such as NF-kappaB and activating protein (AP-1). The effect of the HO system in end-organ damage in mineralocorticoid-induced hypertension has not been fully characterized. In this study, the administration of the HO inducer hemin lowered blood pressure (191 vs. 135 mmHg; n = 22, P < 0.01), increased creatinine clearance, and reduced kidney hypertrophy proteinuria, albuminuria, and histopathological lesions, including glomerular hypertrophy, glomerulosclerosis, tubular dilation, tubular cast formation, and interstitial mononuclear cell infiltration in nephrectomy/DOCA-high-salt-hypertension. The renoprotection was accompanied by reduced levels of NF-kappaB, AP-1, fibronectin, transforming growth factor (TGF)-beta, and 8-isoprostane, a marker of oxidative stress. Correspondingly, a robust increase in total antioxidant capacity, HO activity, cGMP, and an antioxidant like ferritin was observed in hemin-treated animals. Our findings suggest that suppression of oxidative/inflammatory insults alongside the corresponding decline of fibronectin and TGF-beta, an activator of extracellular matrix proteins, may account for the attenuation of renal histopathological lesions and the antihypertrophic effects of hemin. The multifaceted interaction among the HO system, TGF-beta, fibronectin, AP-1, and NF-kappaB may be explored to design new drugs against end-stage-organ damage.
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PMID:Hemin therapy attenuates kidney injury in deoxycorticosterone acetate-salt hypertensive rats. 1911 43


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