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)

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

The heart constitutively expresses heme oxygenase (HO)-2, which catabolizes heme-containing proteins to produce biliverdin and carbon monoxide (CO). The heart also contains many possible substrates for HO-2 such as heme groups of myoglobin and cytochrome P-450s, which potentially could be metabolized into CO. As a result of observations that CO activates guanylyl cyclase and induces vascular relaxation and that HO appears to confer protection from ischemic injury, we hypothesized that the HO-CO pathway is involved in ischemic vasodilation in the coronary microcirculation. Responses of epicardial coronary arterioles to ischemia (perfusion pressure approximately 40 mmHg; flow velocity decreased by approximately 50%; dL/dt reduced by approximately 60%) were measured using stroboscopic fluorescence microangiography in 34 open-chest anesthetized dogs. Ischemia caused vasodilation of coronary arterioles by 36 +/- 6%. Administration of N(G)-monomethyl-L-arginine (L-NMMA, 3 micromol.kg(-1).min(-1) intracoronary), indomethacin (10 mg/kg iv), and K(+) (60 mM, epicardial suffusion) to prevent the actions of nitric oxide, prostaglandins, and hyperpolarizing factors, respectively, partially inhibited dilation during ischemia (36 +/- 6 vs. 15 +/- 4%; P < 0.05). The residual vasodilation during ischemia after antagonist administration was inhibited by tin mesoporphyrin IX (SnMP, 10 mg/kg iv), which is an inhibitor of HO (15 +/- 4 vs. 7 +/- 2%; P < 0.05 vs. before SnMP). The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10(-5) M, epicardial suffusion) also inhibited vasodilation during ischemia in the presence of L-NMMA with indomethacin and KCl. Moreover, administration of heme-L-arginate, which is a substrate for HO, produced dilation after ischemia but not after control conditions. We conclude that during myocardial ischemia, HO-2 activation can produce cGMP-mediated vasodilation presumably via the production of CO. This vasodilatory pathway appears to play a backup role and is activated only when other mechanisms of vasodilation during ischemia are exhausted.
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PMID:In vivo role of heme oxygenase in ischemic coronary vasodilation. 1514 58

Induction of heme oxygenase (HO)-1 may confer hepatocellular protection, e.g., in reperfusion injury. Previous reports suggest that intracellular cAMP up-regulates HO-1. The aim of the present study was to assess the role of adrenoceptor agonists as a means to induce HO-1 and to assess molecular mechanisms of HO-1 gene expression by adrenoceptor agonists. Induction of HO-1 in primary cultures of hepatocytes and in rat liver in vivo was assessed by Northern blot, Western blot, and immunohistochemistry. The beta-receptor agonists (+/-)isoproterenol and (-)isoproterenol induced HO-1 in primary cultures of hepatocytes but not the inactive enantiomer (+)isoproterenol. No induction of HO-1 was observed after alpha1, alpha2, beta2, or beta 3 agonists. beta1-Receptor agonists dobutamine and xamoterol induced HO-1 dose dependently, whereas the beta1-receptor antagonist metoprolol attenuated HO-1 induction by beta1-receptor agonists. Furthermore, 8 Br-cAMP and forskolin induced HO-1. Inhibition of protein kinase A (PKA) abolished induction by dobutamine and 8 Br-cAMP. Parallel changes were observed for the transcription factor AP-1. In vivo infusion of dobutamine for 6 h induced HO-1 in rat livers. Immunohistochemical detection of HO-1 revealed a pericentral expression pattern of HO-1 in hepatocytes, i.e., the area at risk for ischemia/reperfusion injury. These results suggest induction of HO-1 by beta1-adrenoceptor agonists via the PKA pathway in hepatocytes, reflecting a potential means for "pharmacological preconditioning."
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PMID:Heme oxygenase-1 gene expression in pericentral hepatocytes through beta1-adrenoceptor stimulation. 1517 40

Ischemia and reperfusion injury (IRI) represents the major problem in clinical liver transplantation. We have shown that transcription of signal transducer and activator of transcription 4 (Stat4) plays a key role in the mechanism of hepatic IRI, whereas local induction of interleukin 13 (IL-13) is cytoprotective. The disruption of innate Toll-like receptor 4 (TLR4) signaling prevents mouse livers from undergoing fulminant IRI. This study analyzes in vivo interplay between innate (TLR4) and adaptive (Stat6) immunity in Ad-IL-13 (recombinant adenovirus encoding IL-13) cytoprotection in hepatic IRI. Using a partial 90-min lobar warm ischemia model, groups of wild-type and Stat6-deficient knockout mice were assessed for the severity of hepatocellular damage at 6 hr postreperfusion. Unlike in wild-type mice, treatment of Stat6 knockout recipients with Ad-IL-13 failed to improve hepatic function/histology. The expression of mRNAs encoding tumor necrosis factor alpha/IL-1 beta and IL-2/interferon gamma remained depressed in the wild-type plus Ad-IL-13 group, but not in the Stat6 knockout plus Ad-IL-13 group. Ad-IL-13 increased antioxidant heme oxygenase 1 (HO-1) expression and prevented TLR4 activation in livers of Stat6-competent (wild-type) mice. In contrast, low HO-1 expression and enhanced TLR4 expression were recorded in Stat6 knockout recipients despite Ad-IL-13 therapy. Thus (1) Stat6 is required for Ad-IL-13 to prevent IRI, and (2) depression of TLR4 activation is Stat6 dependent. In conclusion, the Stat6 pathway operates as a key negative regulator in the hepatic inflammatory ischemia-reperfusion response. This study outlines requirements for Ad-IL-13 use to maximize the organ donor pool through the use of liver transplants despite prolonged ischemia.
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PMID:Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection. 1524 29

High levels of free heme are found in pathological states of increased hemolysis, such as sickle cell disease, malaria, and ischemia reperfusion. The hemolytic events are often associated with an inflammatory response that usually turns into chronic inflammation. We recently reported that heme is a proinflammatory molecule, able to induce neutrophil migration, reactive oxygen species generation, and IL-8 expression. In this study, we show that heme (1-50 microM) delays human neutrophil spontaneous apoptosis in vitro. This effect requires heme oxygenase activity, and depends on reactive oxygen species production and on de novo protein synthesis. Inhibition of ERK and PI3K pathways abolished heme-protective effects upon human neutrophils, suggesting the involvement of the Ras/Raf/MAPK and PI3K pathway on this effect. Confirming the involvement of these pathways in the modulation of the antiapoptotic effect, heme induces Akt phosphorylation and ERK-2 nuclear translocation in neutrophils. Futhermore, inhibition of NF-kappa B translocation reversed heme antiapoptotic effect. NF-kappa B (p65 subunit) nuclear translocation and I kappa B degradation were also observed in heme-treated cells, indicating that free heme may regulate neutrophil life span modulating signaling pathways involved in cell survival. Our data suggest that free heme associated with hemolytic episodes might play an important role in the development of chronic inflammation by interfering with the longevity of neutrophils.
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PMID:Heme inhibits human neutrophil apoptosis: involvement of phosphoinositide 3-kinase, MAPK, and NF-kappaB. 1526 37

Efficient functioning of maintenance and repair processes seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed "vitagenes," among these, the heat shock system, a highly conserved mechanism responsible for the preservation and repair of cellular macromolecules, such as proteins, RNAs, and DNA. Recent studies have shown that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including ischemia and reperfusion damage, inflammation, cancer, as well as metabolic and neurodegenerative disorders. Recently, the involvement of the heme oxygenase (HO) pathway in antidegenerative mechanisms has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein. HO induction occurs together with the induction of other heat shock proteins during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms, via the heat shock response, through nutritional antioxidants or pharmacological compounds, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistently, by maintaining or recovering the activity of vitagenes, it is feasible to delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.
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PMID:Redox regulation in neurodegeneration and longevity: role of the heme oxygenase and HSP70 systems in brain stress tolerance. 1534 50

The induction of heme oxygenase (HO), the rate limiting enzyme in the conversion of heme into carbon monoxide (CO) and biliverdin, limits liver injury following remote trauma such as hind limb ischemia/reperfusion (I/R). Using intravital video microscopy, we tested the hypothesis that inhaled CO (250 ppm) would mimic HO-derived liver protection. Hind limb I/R significantly decreased sinusoidal diameter and volumetric flow, increased leukocyte accumulation within sinusoids, increased leukocyte rolling and adhesion within postsinusoidal venules, and significantly increased hepatocyte injury compared with naive animals. Inhalation of CO alone did not alter any microcirculatory or inflammatory parameters. Inhalation of CO following I/R restored volumetric flow, decreased stationary leukocytes within sinusoids, decreased leukocyte rolling and adhesion within postsinusoidal venules, and significantly reduced hepatocellular injury following hind limb I/R. HO inhibition did not alter microcirculatory parameters in naive mice, but did increase inflammation, as well as increase hepatocyte injury following hind limb I/R. Inhalation of CO during HO inhibition significantly reduced such microcirculatory deficits, hepatic inflammation, and injury in response to hind limb I/R. In conclusion, these results suggest that HO-derived hepatic protection is mediated by CO, and inhalation of low concentrations of CO may represent a novel therapeutic approach to prevent remote organ injury during systemic inflammatory response syndrome, or SIRS.
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PMID:Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion. 1551 2

During the transplant process, the graft is exposed to numerous events, which may enhance its immunogenicity. In particular, factors related to brain death, such as hemodynamic instability and systemic release of cytokines, cold preservation on harvesting, and reperfusion injury, are known to accumulate in harm, conveying a proinflammatory state to the graft before transplant. Alloimmune reactivity is initiated when the host immune system detects non-self-antigens in the context of "danger signals." Eliminating these danger signals by modifying the graft before transplant has the potential to attenuate the alloimmune response. The molecules, which mediate danger signals, have not yet been fully identified. Free oxygen radicals and interferon-gamma are important candidates. One of the most important protective mechanisms against oxidative stress is the heme oxygenase 1 system. Up-regulation of heme oxygenase 1 in grafts has been shown to prevent ischemia-reperfusion damage and improve long-term graft survival in various transplant models. The benefit of blocking the action of interferon-gamma in kidney transplants is less clear because the compound plays such a complex and pivotal role in the immune response, and experimental data with interferon-gamma receptor knockout mice are conflicting. It has recently become clear that catecholamines are important graft-modifying agents. Dopamine is capable of stimulating the induction of protective enzymes like heme oxygenase-1 (HO-1) rendering the organ more resistant to the insult of ischemia/reperfusion and inflammation. Retrospective clinical data suggest that treatment of brain-dead organ donors with catecholamines is associated with less rejection and a better long-term graft survival of kidneys transplanted from these donors. Catecholamines can also modulate cytokine production and prevent cold-induced damage. Other substances, such as proteoglycans and phosphatidylethanolamine-bound hyaluronic acid, may interfere with the actions of interferon-gamma. Further studies of these compounds in experimental animal models and in prospective randomized clinical trials will help establish their efficacy in donor pretreatment. It is important to underscore that donor pretreatment will have great advantages for the recipient because an improved long-term graft survival could thus be achieved cost-efficiently and without great effort or side effects.
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PMID:Preconditioning strategies to limit graft immunogenicity and cold ischemic organ injury. 1555 55

Intermittent clamping of the porta hepatis (PHC) is commonly performed during liver surgery to reduce blood loss and has been reported to precondition livers resulting in improved outcome after liver surgery (humans) and transplantation (animals). This study investigated the early expression of cytoprotective stress proteins during ischemia-reperfusion induced by PHC. Liver samples were taken before and after each event in a two-cycle ischemia-reperfusion protocol using 15 minutes of PHC followed by 5 minutes of reperfusion. Liver tissue was analyzed by real-time polymerase chain reaction for heme oxygenase (HO)-1 and heat shock protein (HSP)-70 mRNA expression. Extracted protein was analyzed by Western blot for HO-1, and HSP-70 and nuclear extracts were analyzed by DNA mobility shift assay for hypoxia inducible factor (HIF)-1alpha and heat shock factor (HSF)-1. Within minutes of PHC, significant increases in HO-1 mRNA expression were detected, and these were maintained throughout the protocol (P < 0.01). Protein expression of HO-1 (P < 0.03) and HO-1 activity (P < 0.05) were similarly increased between the start and end of ischemia- reperfusion (40 minutes). Binding of active HIF-1alpha to its consensus sequence was increased within 15 minutes of the start of the ischemia-reperfusion cycle. Although evidence of the transcriptionally active form of HSF-1 was detected at the same time point, this was not reflected in measurable changes in HSP-70 mRNA or protein. In conclusion, expression of the cytoprotective protein HO-1 is significantly up-regulated in the liver within minutes of PHC. It is likely that HO-1 contributes to the early protective effects of ischemic preconditioning.
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PMID:Early stress protein gene expression in a human model of ischemic preconditioning. 1559 12

Both carbon monoxide (CO) and biliverdin, products of heme degradation by heme oxygenase, have been shown to attenuate ischemia/reperfusion (I/R) injury. We hypothesized in this study that dual-treatment with CO and biliverdin would induce enhanced protective effects against cold I/R injury. Heterotopic heart and orthotopic kidney transplantation were performed in syngeneic Lewis rats after 24-h cold preservation in UW solution. While monotherapy with CO (20 ppm) or biliverdin (50 mg/kg, ip) did not alter the survival of heart grafts, dual-treatment increased survival to 80% from 0% in untreated recipients, with a significant decrease of myocardial injury and improved cardiac function. Similarly, dual-treatment significantly improved glomerular filtration rates of renal grafts and prolonged recipient survival compared to untreated controls. I/R injury-induced up-regulation of pro-inflammatory mediators (e.g. TNF-alpha, iNOS) and extravasation of inflammatory infiltrates were significantly less with dual-treatment than untreated controls. In addition, dual-treatment was effective in decreasing lipid peroxidation and improving graft blood flow through the distinctive action of biliverdin and CO, respectively. The study shows that the addition of byproducts of heme degradation with different mechanisms of action provides enhanced protection against transplant-associated cold I/R injury of heart and kidney grafts.
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PMID:Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both. 1564 87


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