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Query: UNIPROT:P06889 (Mol)
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Enterally administered, heme is a good source of iron in humans and other animals, but the metabolism of heme by enterocytes has not been fully characterized. Caco-2 cells in culture provide a useful model for studying cells that resemble small intestinal epithelium, both morphologically and functionally. In this paper we show that heme oxygenase, the rate-controlling enzyme of heme catabolism, is present in abundance in Caco-2 cells, and that levels of its mRNA and activity can be increased by exposure of the cells to heme or metal ions (cadmium, cobalt). Caco-2 cells also contain biliverdin reductase activity which, in the basal state, is similar to that of heme oxygenase (approximately 40 pmole of product per mg protein per minute); however, when heme oxygenase is induced, biliverdin reductase may become rate-limiting for bilirubin production.
Mol Cell Biochem 1993 Dec 08
PMID:Induction of heme oxygenase in intestinal epithelial cells: studies in Caco-2 cell cultures. 817 32

The human monocytic leukemia cell line THP-1 differentiates into macrophage-like cells when treated with a variety of agents, including 12-O-tetradecanoylphorbol-13-acetate (TPA). We show here that during this process, the expression of heme oxygenase, a rate-limiting enzyme in heme catabolism, is induced. Treatment with TPA increases heme oxygenase mRNA in other myelomonocytic cell lines also, but not in cell lines of other lineages, such as HeLa cells. Increased heme oxygenase activity may represent one of the functions of activated macrophages, which sequestrate senescent erythrocytes and degrade heme derived from hemoglobin. This cell-type-specific induction by TPA treatment further investigated with respect to transcriptional regulation. We defined a cis-regulatory element, 5'-GTCATATGAC-3', located in the 5'-flanking region (positions -156 to -147) of the human heme oxygenase gene, which confers inducibility by TPA in THP-1 cells but not in HeLa cells. Nuclear proteins that bind to this element, which may be responsible for the cell specificity, were identified in THP-1 nuclear extracts. This element contains the consensus motif CANNTG, to which a large family of basic helix-loop-helix proteins binds. Our results suggest a novel mechanism of TPA-mediated transcriptional regulation in myelomonocytic cell lines.
Mol Cell Biol 1993 Dec
PMID:Identification of a cis-regulatory element and putative trans-acting factors responsible for 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated induction of heme oxygenase expression in myelomonocytic cell lines. 824 3

The effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] on ionic current responses produced by ionotropic glutamate and gamma-aminobutyric acid (GABA)A receptor activation in the nucleus of the tractus solitarius (NTS) were examined. Recordings were made in the dorsomedial subdivision of the NTS adjacent to the area postrema in transverse brainstem slices of the rat. (1S,3R)-ACPD produced a small inward current (IACPD) associated with a decrease in conductance in approximately 50% of recordings. Monosynaptic excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation in the region of the tractus solitarius in the presence of D-amino-5-phosphonopentanoic acid and bicuculline were reversibly reduced by (1S,3R)-ACPD in > 90% of cells. The inward current evoked by pressure application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (IAMPA) was potentiated in the presence of (1S,3R)-ACPD, whereas the outward current evoked by the GABAA receptor agonist muscimol (IMUSC) was inhibited. We have previously demonstrated that these effects may involve the activation of soluble guanylate cyclase. The diffusible second messengers nitric oxide and carbon monoxide are known to activate soluble guanylate cyclase. The nitric oxide synthase inhibitor L-omega-nitroarginine failed to inhibit responses to (1S,3R)-ACPD. The selective heme oxygenase inhibitor Zn-protoporphyrin-IX, which would be expected to block the production of carbon monoxide, antagonized the effects of (1S,3R)-ACPD on EPSCs, IAMPA, and IMUSC. However, IACPD was not blocked. A relatively inactive metalloprotoporphyrin, Cu-protoporphyrin-IX was ineffective. A cell-permeant form of cGMP, 8-Br-cGMP inhibited EPSCs, IAMPA, and IMUSC in the presence of Zn-protoporphyrin-IX but did not induce an inward current. These results further support the hypothesis that multiple metabotropic glutamate receptors exist in the NTS, and they suggest that one of these may be coupled to the activation of a soluble guanylate cyclase via the liberation of an easily diffusible second messenger such as carbon monoxide.
Mol Pharmacol 1993 Jun
PMID:Zinc protoporphyrin-IX blocks the effects of metabotropic glutamate receptor activation in the rat nucleus tractus solitarii. 839 Nov 21

Redox regulation of DNA-binding proteins through the reversible oxidation of key cysteine sulfhydryl groups has been demonstrated to occur in vitro for a range of transcription factors. The direct redox regulation of DNA binding has not been described in vivo, possibly because most protein thiol groups are strongly buffered against oxidation by the highly reduced intracellular environment mediated by glutathione, thioredoxin, and associated pathways. For this reason, only accessible protein thiol groups with high thiol-disulfide oxidation potentials are likely to be responsive to intracellular redox changes. In this article, we demonstrate that zinc finger DNA-binding proteins, in particular members of the Sp-1 family, appear to contain such redox-sensitive -SH groups. These proteins displayed a higher sensitivity to redox regulation than other redox-responsive factors both in vitro and in vivo. This effect was reflected in the hyperoxidative repression of transcription from promoters with essential Sp-1 binding sites, including the simian virus 40 early region, glycolytic enzyme, and dihydrofolate reductase genes. Promoter analyses implicated the Sp-1 sites in this repression. Non-Sp-1-dependent redox-regulated genes including metallothionein and heme oxygenase were induced by the same hyperoxic stress. The studies demonstrate that cellular redox changes can directly regulate gene expression in vivo by determining the level of occupancy of strategically positioned GC-binding sites.
Mol Cell Biol 1996 Mar
PMID:Physical and functional sensitivity of zinc finger transcription factors to redox change. 862 48

To examine the intracellular signaling mechanism of NO in ischemic myocardium, isolated working rat hearts were made ischemic for 30 min followed by 30 min of reperfusion. A separate group of hearts were pre-perfused with 3 mM L-arginine in the presence or absence of 650 microM of protoporphyrin, a heme oxygenase inhibitor for 10 min prior to ischemia. The release of NO was monitored using an on-line amperometric sensor placed into the right atrium. The aortic flow and developed pressure were examined to determine the effects of L-arginine on ischemic/reperfusion injury. Induction for the expression of heme oxygenase was studied by Northern hybridization. For signal transduction experiments, sarcolemmal membranes were radiolabeled by perfusing the isolated hearts with [3H] myoinositol and [14C] arachidonic acid. Biopsies were processed to determine the isotopic incorporation into various phosphoinositols as well as phosphatidic acid and diacylglycerol. cGMP was assayed by radioimmunoassay and SOD content was determined by enzymatic analysis. The release of NO was diminished following ischemia and reperfusion and was augmented by L-arginine. L-arginine reduced ischemic/reperfusion injury as evidenced by the enhanced myocardial functional recovery. Protoporphyrin modulated the effects of L-arginine. cGMP, which was remained unaffected by ischemia and reperfusion, was stimulated significantly after L-arginine treatment. The NO-mediated augmentation of cGMP was reduced by protoporphyrin suggesting that part of the effects may be mediated by CO generated through the heme oxygenase pathway. Reperfusion of ischemic myocardium resulted in significant accumulation of radiolabeled inositol phosphate, inositol bisphosphate, and inositol triphosphate. Isotopic incorporation of [3H] inositol into phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-bisphosphate was increased significantly during reperfusion. Reperfusion of the ischemic heart prelabeled with [14C] arachidonic acid resulted in modest increases in [14C] diacylglycerol and [14C] phosphatidic acid. Pretreatment of the heart with L-arginine significantly reversed this enhanced phosphodiesteratic breakdown during ischemia and early reperfusion. However, at the end of the reperfusion the inhibitory effect of L-arginine on the phosphodiesterases seems to be reduced. In L-arginine treated hearts, SOD activity was progressively decreased with the duration of reperfusion time. The results suggests for the first time that NO plays a significant role in transmembrane signaling in the ischemic myocardium. This signaling appears to be on- and off- nature, and linked with SOD content of the tissue. The signaling is transmitted via cGMP and opposes the effects of phosphodiesterases by inhibiting the ischemia/reperfusion-induced phosphodiesteratic breakdown. Our results also suggest that NO activates heme oxygenase which further stimulates the production of cGMP presumably by CO signaling. Thus, NO not only potentiates cGMP mediated intracellular signaling, it also functions as a retrograde messenger for CO signaling in heart.
Mol Cell Biochem
PMID:Nitric oxide--a retrograde messenger for carbon monoxide signaling in ischemic heart. 873 31

A variety of stress including oxidative stress, hyperthermia and heavy metals can induce the expression of haem oxygenase in mammalian tissue. In this study we examined whether an ischemic stress could induce haem oxygenase in heart. Isolated perfused rat hearts were subjected to either 5 or 20 min of ischemia followed by 15, 30, 45 and 60 min of reperfusion in each case. The results of our study indicate that haem oxygenase is not induced by ischemia, but can be induced by reperfusion. The induction of haem oxygenase is a function of the duration of reperfusion. This induction can be blocked by pre-perfusing the hearts with oxygen free radical scavengers, superoxide dismutase (SOD) and catalase. Haem oxygenase was also induced in the hearts by perfusing them with oxygen free radical generating system. This induction was also blocked by SOD and catalase. Immunohistochemical localization revealed that haem oxygenase-1 is primarily accumulated in the perivascular region and in the cardiomyocytes. This suggests that it is oxygen free radicals that is produced during the reperfusion is the stimulus for the expression of haem oxygenase in the ischemic/reperfused myocardium.
J Mol Cell Cardiol 1996 Jun
PMID:Induction of the haem oxygenase gene expression during the reperfusion of ischemic rat myocardium. 878 67

The inducible form of heme oxygenase (heme oxygenase-1) is a heat shock protein 32 (HSP32) whose expression is induced by numerous agents, including heme compounds and heavy metals, and during oxidative stress. The purpose of this study was to examine whether heme oxygenase-1 is induced during primary cell culture of cardiomyocytes and the relation of heme oxygenase-1 expression to oxidative stress levels. Western blot analysis and reverse transcription-polymerase chain reaction analysis showed heme oxygenase-1 expression 12-48 h after isolation of rat neonatal cardiomyocyte for culture. Its expression was barely detected immediately after isolation. Actinomycin D or cycloheximide completely suppressed such expression. Myocardial cells were exposed to oxidative stress during the first 12 h after isolation as assessed by their glutathione redox state; the ratio of reduced glutathione/oxidized glutathione was less than 10. The expression of heme oxygenase-1 was significantly reduced by treatment with reduced glutathione (58% reduction, P < 0.05), but markedly increased by treatment with hydrogen peroxide (65% increase, P < 0.05) 12 h after isolation. Expression of heat shock protein 70 was not significantly changed during primary culture incubation. Results indicate that heme oxygenase-1 is expressed during primary culture of cardiomyocytes. Its expression is closely related to the oxidative stress level of the cultured cells.
J Mol Cell Cardiol 1996 Sep
PMID:Heme oxygenase-1 expression and its relation to oxidative stress during primary culture of cardiomyocytes. 889 43

Recent evidence suggests that the gas nitric oxide can modulate the secretion of a number of hypothalamic hormones, and may be co-localized particularly to oxytocin-containing neurons. Another gas, carbon monoxide (CO), has also been suggested to play a role in neural signaling in the brain, and the synthetic enzyme responsible for the generation of carbon monoxide has been reported to be present in the rat hypothalamus. In this study, we have therefore investigated whether CO has the ability to modify the release of oxytocin from acute rat hypothalamic explants. Hemin, a specific CO precursor through the enzyme heme oxygenase (the enzymatic pathway synthesizing endogenous CO, was found to inhibit KCl-stimulated oxytocin release, with a maximal effect at 10(-5) M, while showing no effect on basal oxytocin secretion. The stimulation of oxytocin by serotonin 10 ng/ml was also significantly antagonized by hemin 10(-7) M. An inhibitor of heme oxygenase, zinc-protoporphyrin-9, had no effect on basal or stimulated oxytocin release. When hemin and zinc-protoporphyrin-9 were given together, the hemin-induced inhibition of oxytocin was completely antagonized by the enzyme inhibitor. Ferrous hemoglobin A0, a substance known to bind CO with high affinity, had no effect on either basal or stimulated oxytocin release, but when hemin and ferrous hemoglobin A0 were given together the hemin-induced inhibition of oxytocin was completely blocked. These findings provide evidence that endogenous CO may play a role in the control of oxytocin release and that, by analogy with nitric oxide, CO may represent a major new neuroendocrine modulator.
Brain Res Mol Brain Res 1996 Dec
PMID:Oxytocin release is inhibited by the generation of carbon monoxide from the rat hypothalamus--further evidence for carbon monoxide as a neuromodulator. 901 87

Heme oxygenase catalyzes the first and rate-controlling step in heme catabolism. One of the two forms of heme oxygenase (heme oxygenase-1) has been shown to be increased by heme, metals, and in some systems, by certain environmental stresses. However, it remains uncertain whether heme induces hepatic heme oxygenase-1 by a general stress response, or a specific heme-dependent cellular response. The work communicated here explores this issue by examining possible mechanisms whereby heme and other metalloporphyrins induce heme oxygenase-1 in normal liver cells. Primary cultures of chick embryo liver cells were tested for their ability to increase heme oxygenase mRNA after exposure to selected metalloporphyrins (heme, chromium mesoporphyrin, cobalt protoporphyrin and manganese protoporphyrin). The ability of antioxidants to decrease metalloporphyrin-mediated induction of heme oxygenase-1 mRNA was also tested. Our results indicate that: 1) the increase in heme oxygenase-1 mRNA mediated by heme or other metalloporphyrins may involve a short-lived protein(s) since the increase was prevented by several inhibitors of protein synthesis; and 2) in normal liver cells, heme-dependent oxidative stress does not play a key role in the heme-mediated induction of heme oxygenase-1. We conclude that heme and other non-heme metalloporphyrins induce heme oxygenase-1 through a mechanism requiring protein synthesis, not because metalloporphyrins increase cellular oxidative or other stress.
Mol Cell Biochem 1997 Apr
PMID:Mechanism of induction of heme oxygenase by metalloporphyrins in primary chick embryo liver cells: evidence against a stress-mediated response. 908 26

Carbon monoxide (CO) shares with nitric oxide (NO) the ability to modulate the release of hypophysiotropic peptides from rat hypothalamic explants. While both gases are believed to act as neural messengers in the brain via the activation of soluble guanylyl cyclase, the latter is almost undetectable in the rat hypothalamus. NO has been shown to exert some of its biological actions through the modulation of prostaglandin endoperoxide synthase (PGHS) activity. We have, therefore, investigated whether CO also can use PGHS as a signaling pathway in the hypothalamus. Endogenous CO is produced in equimolar amounts with biliverdin (BV) by the catabolism of hemin through heme oxygenase (HO). Hemin, two inhibitors of HO, zinc-protoporphyrin-9 (ZnPP9) and tin-mesoporphyrin-9 (SnMP9), ferrous hemoglobin (Hb), indomethacin and dexamethasone (DEX) were used as pharmacological tools. Prostaglandin E2 (PGE2) released from rat hypothalamic explants or primary cultures of hypothalamic astrocytes was taken as a marker of PGHS activity. It was found that: (1) hemin evokes an increase in PGE2 release from hypothalamic explants; (2) this effect is counteracted by ZnPP9, SnMP9, Hb and indomethacin; (3) the metallo-porphyrins and indomethacin, but not Hb, are also able to inhibit basal PGE2 release from hypothalamic explants; and (4) dexamethasone does not inhibit, and even potentiates, the stimulatory effect of hemin on PGE2 release from hypothalamic astrocytes. The evidence presented here suggests that the catabolism of endogenous or exogenously added hemin is associated with an increase in PGE2 production in the rat hypothalamus. This effect can be attributed to the formation of CO, since the other end-product of HO, BV, does not enhance PGE2 release. Thus, at least some of the biological effects of CO at the hypothalamic level might be mediated by the activation of the PGHS pathway.
Brain Res Mol Brain Res 1997 May
PMID:Evidence that carbon monoxide stimulates prostaglandin endoperoxide synthase activity in rat hypothalamic explants and in primary cultures of rat hypothalamic astrocytes. 914 4


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