Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The export of certain nuclear proteins is involved in the regulation of various nuclear functions, including transcription. In some cases, the export of target proteins is induced upon environmental or cellular cues, resulting in conditional gene expression. The small Maf proteins appear to be critical regulators of heme oxygenase (HO)-1, an anti-oxidant defense enzyme that degrades heme into iron, carbon monoxide, and biliverdin. Although ho-1 is repressed by Bach1/small Maf heterodimers, it is activated by Nrf2/small Maf heterodimers, indicating that Bach1 and Nrf2 compete with each other. We anticipated that the nuclear concentration of Bach1 might be regulated to ensure that the entire system effectively responds to various stimuli. We carried out detailed domain analysis of Bach1 in an effort to understand how various inducers of HO-1 inactivate Bach1. We show here that cadmium, a strong inducer of HO-1, activates the nuclear export of Bach1. This cadmium-induced export of Bach1 was mediated in trans by its C-terminal region that is conserved between Bach1 and Bach2. The nuclear export of Bach2 was also induced by cadmium, indicating that the cadmium responsibility is shared between Bach1 and Bach2. The nuclear export of Bach1 was dependent on Crm1/Exportin-1 as well as the extracellular signal-regulated kinase-1/2 (ERK1/2) activity. These results indicate that the nuclear export of Bach1 constitutes an important regulatory mechanism to relieve the Bach1-mediated repression of genes such as ho-1.
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PMID:Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene. 1450 88

Pyelonephritis is a risk factor for renal tubular epithelial cell damage in children. The inter- and intracellular regulator nitric oxide (NO) plays a role in the modulation of cellular viability in urinary tract infections, but the role of the NO pathway in renal proximal tubular-cell death remains unclear. The present study demonstrates that, in renal epithelial cells undergoing death mediated by Escherichia coli strain ARD6 serotype O6K13H1 (O6), levels of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and inducible NO synthase (iNOS) proteins are up-regulated, but levels of endothelial NO synthase are down-regulated. When NO synthase (NOS) activity is inhibited by the specific inhibitor of NOS or mitogen-activated protein kinase kinase, cells are prevented from death. Moreover, down-regulating protein 53 (p53) does not prevent the cells from dying, although p53 is up-regulated in O6-exposed cells. Up-regulation of heme oxygenase (HO)-1 by sodium nitroprusside or by the specific activator hemin inhibits cell death. In conclusion, the activation of ERK mediates O6 toxin-mediated renal cell death via induction of iNOS. Stimulation of HO-1 protects cells against death.
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PMID:Activation of extracellular signal-regulated kinase mediates apoptosis induced by uropathogenic Escherichia coli toxins via nitric oxide synthase: protective role of heme oxygenase-1. 1519 52

The induction of heme oxygenase-1 (HO-1) is widely recognized as an effective cellular strategy to counteract a variety of stressful events. We have shown that curcumin and caffeic acid phenethyl ester, two naturally occurring phytochemicals that possess antioxidant, anti-inflammatory, and anticarcinogenic activities, induce HO-1 in many cell types. This suggests that stimulation of HO-1 could partly underlie the beneficial effects exerted by these plant-derived constituents. Here we examined the ability of additional plant constituents to up-regulate heme oxygenase activity and HO-1 in aortic endothelial cells. Incubation of endothelial cells with a series of polyphenolic chalcones (5-50 microM) resulted in increased heme oxygenase activity; interestingly, the chemical structure dictated the pattern of heme oxygenase induction, which was unique to each particular compound employed. We also found that rosolic acid, a constituent isolated from the rhizome of Plantago asiatica L. dramatically increased HO-1 in a concentration- and time-dependent manner. Severe cytotoxicity was observed after prolonged exposure (24 or 48 h) of cells to curcumin and caffeic acid phenethyl ester, whereas 2'-hydroxychalcone and rosolic acid did not affect cell viability. By using different mitogen-activated protein kinase inhibitors, we determined that the extracellular signal-regulated kinase, p38, and c-Jun NH(2)-terminal protein kinase pathways play only a minor role in the induction of HO-1 by rosolic acid and 2'-hydroxychalcone. On the other hand, increased intra- and extracellular thiols markedly reduced the rise in heme oxygenase activity elicited by rosolic acid. Thus, this study identified novel plant constituents that highly induce HO-1 in endothelial cells and investigated some of the mechanisms involved in this effect.
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PMID:Differential activation of heme oxygenase-1 by chalcones and rosolic acid in endothelial cells. 1553 27

Oxidized low-density lipoproteins (LDL) play a central role in atherogenesis and induce expression of the antioxidant stress protein heme oxygenase 1 (HO-1). In the present study we investigated induction of HO-1 and adaptive increases in reduced glutathione (GSH) in human aortic smooth muscle cells (SMC) in response to moderately oxidized LDL (moxLDL, 100 microg protein/ml, 24 h), a species containing high levels of lipid hydroperoxides. Expression and activity of HO-1 and GSH levels were elevated to a greater extent by moxLDL than highly oxidized LDL but unaffected by native or acetylated LDL. Inhibitors of protein kinase C (PKC) or mitogen-activated protein kinases (MAPK) p38(MAPK) and MEK or c-jun-NH2-terminal kinase (JNK) significantly attenuated induction of HO-1. Phosphorylation of p38(MAPK), extracellular signal-regulated kinase (ERK1/2), or JNK and nuclear translocation of the transcription factor Nrf2 were enhanced following acute exposure of SMC to moxLDL (100 microg protein/ml, 1-2 h). Pretreatment of SMC with the antioxidant vitamin C (100 microM, 24 h) attenuated the induction of HO-1 by moxLDL. Native and oxidized LDL did not alter basal levels of intracellular ATP, mitochondrial dehydrogenase activity, or expression of the lectin-like oxidized LDL receptor (LOX-1) in SMC. These findings demonstrate for the first time that activation of PKC, p38(MAPK), JNK, ERK1/2, and Nrf2 by oxidized LDL in human SMC leads to HO-1 induction, constituting an adaptive response against oxidative injury that can be ameliorated by vitamin C.
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PMID:Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2. 1596 14

Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signal-regulated kinase (ERK) activation, Egr-1 expression, and Erg DNA-binding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-alpha. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxia-induced Egr-1 mRNA expression was ERK-dependent, and CO-mediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with l-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP/protein kinase A- and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.
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PMID:Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. 1655 42

Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO.
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PMID:Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. 1678 59

Proliferation of hepatic stellate cells (HSCs) is central for the development of fibrosis during liver injury. We have shown previously that butein (3,4,2',4'-tetrahydroxychalcone) suppresses myofibroblastic differentiation of rat HSCs. Our aim in this study was to determine whether a new synthetic chalcone derivative, 2',4',6'-tris(methoxymethoxy) chalcone (TMMC) inhibits HSC proliferation induced by serum- or platelet-derived growth factor (PDGF). TMMC significantly inhibited growth factor-induced HSC proliferation. The inhibition of PDGF-induced proliferation by TMMC was associated with the phosphatidylinositol 3-kinase-Akt-p70(S6K) pathways. TMMC induced the expression of heme oxygenase 1 (HO-1) in HSCs. Using the chemical inhibitor tin protoporphyrin, we also found that the inhibitory action of TMMC on PDGF-induced proliferation is mediated by HO-1. Glutathione (GSH) depletion produced by TMMC activated extracellular signal-regulated kinase (ERK), which led to c-Fos expression and transactivation of activator protein 1 (AP-1) and HO-1 gene expression in the HSCs. These results demonstrate that TMMC preferentially activates ERK and that this activation leads to the transcriptional activation of AP-1 and consequently to HO-1 expression. HO-1 expression might be responsible for the antiproliferative effect of TMMC on HSCs.
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PMID:2',4',6'-Tris(methoxymethoxy) chalcone attenuates hepatic stellate cell proliferation by a heme oxygenase-dependent pathway. 1698 36

The development of carbon monoxide-releasing molecules (CO-RMs) in recent years helped to shed more light on the diverse range of anti-inflammatory and cytoprotective activities of CO gas. In this study, we examined the effect of a ruthenium-based water-soluble CO carrier (CORM-3) on lipopolysaccharide (LPS)- and interferon-gamma (INF-gamma)-induced inflammatory responses in BV-2 microglial cells and explored the possible mechanisms of action. BV-2 microglial cells were stimulated with either LPS or INF-gamma in the presence of CORM-3 and the inflammatory response evaluated by assessing the effect on nitric oxide production (nitrite levels) and tumor necrosis factor-alpha (TNF-alpha) release. Similar experiments were also performed in the presence of inhibitors of guanylate cyclase (ODQ), NO synthase (L-NAME), heme oxygenase activity (tin protoporphyrin IX) or various mitogen-activated protein kinase (MAPK) inhibitors. CORM-3 significantly attenuated the inflammatory response to LPS and INF-gamma as evidenced by a significant reduction (p < 0.001) in nitrite levels and TNF-alpha production (P < 0.05). Such effect was maintained in the presence of ODQ, L-NAME or tin protoporphyrin without showing any cytotoxicity. The use of an inactive form of CORM-3 that does not contain carbonyl groups (Ru(DMSO)(4)Cl(2) failed to inhibit the increase in inflammatory markers suggesting that liberated CO mediates the observed effects. In addition, inhibition of phosphatidylinositol-3-phosphate kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways seemed to amplify the anti-inflammatory effect of CORM-3, particularly in cells stimulated with INF-gamma. These results suggest that the anti-inflammatory action of CORM-3 could be exploited to mitigate microglia activation in neuro-inflammatory diseases.
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PMID:A carbon monoxide-releasing molecule (CORM-3) attenuates lipopolysaccharide- and interferon-gamma-induced inflammation in microglia. 1733 83

The vascular endothelial growth factor (VEGF) induces angiogenesis in ischemic or inflamed tissues during tumor growth. 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor (PPAR) gamma, has been reported to upregulate VEGF synthesis through the induction of heme oxygenase (HO)-1. In this work, we found that treatment of human breast cancer (MCF-7) cells with 15d-PGJ2 led to time-dependent increases in the expression of HO-1. The PPAR gamma antagonist GW9662 and N-acetylcysteine failed to block induction of HO-1 by 15d-PGJ2. Elevated expression or activity of HO-1 has been reported to stimulate proliferation and to accelerate angiogenesis in several tumor cells. The induction of HO-1 expression preceded the upregulation of VEGF in MCF-7 cells stimulated with 15d-PGJ2. In another experiment, 15d-PGJ2 induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) in 12 h. Treatment of MCF-7 cells with U0126 or transient transfection with dominant negative ERK (DN-ERK) abrogated 15d-PGJ2-induced VEGF expression. To determine whether the induction of HO-1 is responsible for ERK1/2 activation, the HO-1 inhibitor, zinc protoporphyrin (ZnPP) was used. The phosphorylation of ERK1/2 by 15d-PGJ2 was abolished by ZnPP. These results suggest that 15d-PGJ2 upregulates VEGF expression via induction of HO-1 and ERK-1 and -2 phosphorylation, which may contribute to increased angiogenesis of the tumor cells.
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PMID:Upregulation of VEGF by 15-deoxy-Delta12,14-prostaglandin J2 via heme oxygenase-1 and ERK1/2 signaling in MCF-7 cells. 1738 82

Piperine is a major component of black pepper, Piper nigrum Linn, used widely in traditional medicine. In this study, we examined whether piperine could protect House Ear Institute-Organ of Corti 1 (HEI-OC1) cells against cisplatin-induced apoptosis through the induction of heme oxygenase (HO)-1 expression. Piperine (10-100 microM) induced the expression of HO-1 in dose- and time-dependent manners. Piperine also induced antioxidant response element-luciferase and translocated nuclear factor-E2-related factor-2 (Nrf2) to nucleus. Piperine activated the c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase and p38 mitogen-activated protein kinase (MAPK) pathways, and the JNK pathway played an important role in piperine-induced HO-1 expression. Piperine protected the cells against cisplatin-induced apoptosis. The protective effect of piperine was abrogated by zinc protoporphyrin IX, an HO inhibitor, and antisense oligodeoxynucleotides against HO-1 gene. These results demonstrate that the expression of HO-1 by piperine is mediated by both JNK pathway and Nrf2, and the expression inhibits cisplatin-induced apoptosis in HEI-OC1 cells.
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PMID:Piperine protects cisplatin-induced apoptosis via heme oxygenase-1 induction in auditory cells. 1741 61


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