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PubMed1999

Cyclooxygenase dependent release of heme from microsomal hemeproteins correlates with induction of heme oxygenase 1 transcription in human fibroblasts.

Induction of heme oxygenase 1 transcription and enzymatic activity is a common response after exposure of cells to various forms of oxidative stress including ultraviolet A radiation (UVA) and hydrogen peroxide. We now show that UVA irradiation or hydrogen peroxide treatment of human skin fibroblasts leads to an immediate release of the heme oxygenase substrate, heme, from microsomal hemeproteins. The release of heme by UVA apparently involves cyclooxygenase activity because it is inhibited by the cyclooxygenase inhibitor indomethacin. We also demonstrate a high degree of correlation between the amount of heme released and the degree of subsequent induction of heme oxygenase 1 transcription following UVA and hydrogen peroxide treatment. We propose that release of heme from microsomal hemeproteins determines the degree of induction of heme oxygenase 1 transcription in human fibroblasts after oxidative stress.

Butylated Hydroxytoluene↗
PubMed1998

Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1.

The contribution of haeme oxygenase-derived carbon monoxide (CO) to the regulation of vascular tone in thoracic aorta was investigated following induction of the inducible isoform of haeme oxygenase (HO-1). Isometric smooth muscle contractions were recorded in isolated rat aortic ring preparations. Rings were incubated in the presence of the nitric oxide (NO) donor S-nitroso-N-acetyl penicillamine (SNAP, 500 microM) for 1 h, then repetitively washed and maintained for a further 4 h prior to producing a concentration-response curve to phenylephrine (PE, 1-3000 nM). Treatment with SNAP resulted in increased mRNA and protein expression of aortic HO-1 and was associated with a significant suppression of the contractile response to PE (P<0.05 vs control). Immunohistochemical staining procedures revealed marked HO-1 expression in the endothelial layer and, to a lesser extent, in smooth muscle cells. Induction of HO-1 in SNAP-treated rings was associated with a higher 14CO release compared to control, as measured by scintillation counting after incubation of aortas with [2-14C]-L-glycine, the precursor of haeme. Guanosine 3',5'-monophosphate (cyclic GMP) content was also greatly enhanced in aortas expressing high levels of HO-1. Incubation of aortic rings with the NO synthase inhibitor, NG-monomethyl-L-arginine (100 microM), significantly (P<0.05) increased the contractile response to PE in controls but failed to restore PE-mediated contractility in SNAP-treated rings. In contrast, the selective inhibitor of haeme oxygenase, tin protoporphyrin IX (SnPP-IX, 10 microM), restored the pressor response to PE in SNAP-treated rings whilst markedly reducing CO and cyclic GMP production. We conclude that up-regulation of the HO-1/CO pathway significantly contributes to the suppression of aortic contractility to PE. This effect appears to be mediated by the elevation of cyclic GMP levels and can be reversed by inhibition of the haeme oxygenase pathway.

Animals↗
PubMed1980

Metal ion interactions in the control of haem oxygenase induction in liver and kidney.

Mn2+ and Zn2+ exhibit a striking ability to block the induction by Sn2+ and Ni2+ of haem oxygenase (EC 1.14.99.3) in kidney. The blocking effects of Mn2+ and Zn2+ were found to be greatest on simultaneous administration, time-dependent when administered up to 8 h before the inducing metal ions, and ineffective when administered as little as 10 min after the inducing metal ions. The decreases in cytochrome P-450 and haem contents and the sequential changes in delta-aminolaevulinate synthase (EC 2.3.1.37) activity that occur concomitant with haem oxygenase induction were largely eliminated with simultaneous or prior treatment with Mn2+ or Zn2+, but not when Mn2+ or Zn2+ was administered after Sn2+ or Ni2+. Mn2+ and Zn2+ did not increase the catabolism of the enzyme in vivo. Zn2+ on simultaneous administration was also able substantially to block the induction of haem oxygenase by Co2+, Cd2+ and Ni2+ in liver. The Zn2+ blockade of Cd2+ induction was examined in detail, and prior or simultaneous administration of Zn2+ was found to be effective in blocking the induction of haem oxygenase and the concomitant decreases in cytochrome P-450 and haem contents, ethylmorphine demethylase activity and the sequential changes in delta-aminolaevulinate synthase activity. Zn2+ administration 10 min or more after Cd2+ was ineffective in preventing the occurrence of these perturbations in haem metabolism. These findings describe a new and striking biological property of Mn2+ and Zn2+, and indicate the existence of significant metal ion interactions in the control of haem metabolism.

5-Aminolevulinate Synthetase↗
PubMed2003

Haem and nitric oxide: synergism in the modulation of the endothelial haem oxygenase-1 pathway.

NO potently up-regulates vascular haem oxygenase-1 (HO-1), an inducible defensive protein that degrades haem to CO, iron and the antioxidant bilirubin. Since several pathological states are characterized by increased NO production and liberation of haem from haem-containing proteins, we examined how NO influences HO-1 induction mediated by haemin. Aortic endothelial cells treated with S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside (SNP) or diethylenetriamine-NONOate (DETA/NO) and haemin exhibited higher levels of haem oxygenase activity compared with cells exposed to NO donors or haemin alone. This was accompanied by a marked increase in bilirubin production and, notably, by a strong magnification of cellular haem uptake. A role for haem metabolites in modulating HO-1 expression by NO was assessed by exposing cells to SNAP, SNP or DETA/NO in medium derived from cells treated with haemin, which contained increased bilirubin levels. This treatment considerably potentiated HO-1 expression and haem oxygenase activity mediated by NO and the use of a haem oxygenase inhibitor abolished this effect. Both iron liberated during haem breakdown and the formation of nitroxyl anion from NO appeared to partially contribute to the amplifying phenomenon; in addition, medium from haemin-treated cells significantly augmented the release of NO by NO donors. Thus we have identified novel mechanisms related to the induction of HO-1 by NO indicating that the signalling actions of NO vary significantly in the presence of haem and haem metabolites, ultimately increasing the defensive abilities of the endothelium to counteract oxidative and nitrosative stress.

Animals↗
PubMed1982

Metal induction of haem oxygenase without concurrent degradation of cytochrome P-450. Protective effects of compound SKF 525A on the haem protein.

The induction of hepatic haem oxygenase (EC 1.14.99.3) by a series of metals, organometals and metalloporphyrins was examined in vivo in the presence of compound SKF 525A, which is known to complex with the prosthetic group of cytochrome P-450. Concurrent administration of SKF 525A and an inducing metal did not affect the extent and time course of haem oxygenase induction. The decrease in cytochrome P-450 content normally associated with metal administration was, however, prevented, indicating that haem oxygenase induction by metals can proceed without the significant labilization of the haem moiety of cytochrome P-450. In addition, the integrity of this haem protein can be maintained by chemical means in the presence of sustained high activities of haem oxygenase.

5-Aminolevulinate Synthetase↗
PubMedDate not supplied

Induction of alpha-calcitonin gene-related peptide mRNA expression in rat dorsal root ganglia by heat stress involves the heme oxygenase-1/carbon monoxide pathway.

SD rats were pretreated with whole body hyperthermia (rectal 42 degrees C) for 15 min. The level of calcitonin gene-related peptide (CGRP) in plasma, and alpha- and beta-CGRP mRNA as well as heme oxygenease-1 and heme oxygenase-2 mRNA in dorsal root ganglia were determined by radioimmunoassay and semi-quantitative reverse-transcription polymerase chain reaction, respectively. Heat stress induced only the expression of alpha-CGRP or heme oxygenease-1 but not beta-CGRP or heme oxygenase-2 mRNA, and the release of CGRP and induction of alpha-CGRP mRNA expression were abolished by pretreatment with Zinc protoporphyrin IX, the heme oxygenase inhibitor, or methylene blue, the inhibitor of soluble guanylate cyclase. These results indicate that induction of alpha-CGRP mRNA expression in rat DRG by heat stress involves the heme oxygenase-1/carbon monoxide pathway.

Animals↗
PubMed2002

Paraquat-generated oxidative stress in rat liver induces heme oxygenase-1 and aminolevulinic acid synthase.

The in vivo effect of the known herbicide, paraquat, on both hepatic oxidative stress and heme metabolism was studied. A marked increase in lipid peroxidation and a decrease in reduced glutathione (GSH) content were observed 1 h after paraquat administration. The activity of liver antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase was decreased 3 h after paraquat injection. Heme oxygenase-1 induction started 9 h after treatment, peaking at 15 h. delta-aminolevulinic acid synthase induction occurred once heme oxygenase had been enhanced, reaching its maximum (1.5-fold of control) at 16 h. delta-aminolevulinic acid dehydratase activity was 40% inhibited at 3 h showing a profile similar to that of GSH, while porphobilinogenase activity was not modified along the whole period of the assay. Administration of alpha-tocopherol (35 mmol/kg body weight) 2 h before paraquat treatment entirely prevented the increase in thiobarbituric acid reactive substances (TBARS) content, the decrease in GSH levels as well as heme oxygenase-1 and delta-aminolevulinic acid synthase induction. This study shows that oxidative stress produced by paraquat leads to an increase in delta-aminolevulinic acid synthase and heme oxygenase-1 activities, indicating that the herbicide affects both heme biosynthesis and degradation.

5-Aminolevulinate Synthetase↗
PubMed1999

The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis.

Heme oxygenase is the rate limiting enzyme in heme degradation to carbon monoxide (CO), iron and bilirubin. The inducible isoform of the protein, heme oxygenase-1 (HO-1), is susceptible to up-regulation by a diverse variety of conditions and agents in mammalian tissue, leading to the common conception that HO-1 is a stress related enzyme. However, as attempts are made to unravel the mechanisms by which HO-1 is induced and as we discover that CO, iron and bilirubin may be important effector molecules, we are learning to appreciate that heme oxygenases may be central to the regulation of many physiological and pathophysiological processes besides their established function in heme catabolism. One such process may be closely linked to nitric oxide (NO). It has been demonstrated that NO and NO donors are capable of inducing HO-1 protein expression, in a mechanism depending on the de novo synthesis of RNA and protein. Thus, it is postulated that NO may serve as a signaling molecule in the modulation of the tissue stress response. This review will highlight the current ideas on the role of CO-heme oxygenase and NO-nitric oxide synthase in cell signaling and discuss how the two systems are interrelated.

Animals↗
PubMed1981

Photo-reversal by monochromatic light of the carbon monoxide-inhibited heme degradation catalyzed by the reconstituted heme oxygenase system.

Photo-reversal of the carbon monoxide inhibition of heme oxygenase reaction by monochromatic light was investigated. Heme degradation in either the microsomal or the reconstituted heme oxygenase system was inhibited by CO. In both systems the extents of Co inhibition were dependent on the CO/O2 ratio and were nearly equal at a given CO/O2 ratio. In the reconstituted heme oxygenase reaction using a highly purified heme oxygenase preparation the relationship between the intensity of light and the degree of reversal of the CO inhibition of heme degradation as expressed in terms of delta K/Kd was not linear, but the tentatively obtained photochemical action spectrum exhibited the peaks of reversal at about 420, 540, 570, and 640 nm and suggested the occurrence of at least two steps of CO inhibition in the overall sequence of heme degradation. One could be ascribed to protoheme and the other was supposed to be the 688 nm compound which is an intermediate locating between hydroxyheme and the biliverdin-iron complex in the sequence of heme degradation.

Animals↗
PubMed1983

A stoichiometric study of heme degradation catalyzed by the reconstituted heme oxygenase system with special consideration of the production of hydrogen peroxide during the reaction.

In heme degradation catalyzed by the reconstituted heme oxygenase system, 8 to 9 mol of dioxygen and 11 to 12 mol of NADPH were consumed per mol of hemin lost, and about half the amount of dioxygen consumed could be accounted for by the production of hydrogen peroxide, which accumulated in the reaction mixture. Production of hydrogen peroxide in the heme oxygenase reaction did not appear to be due to the bimolecular dismutation of superoxide anions but rather seemed to be due to dissociation of a "peroxo" species formed on heme or intermediates of heme degradation. The hydrogen peroxide produced appeared to cause a considerable degree of non-specific degradation of heme (not leading to the formation of biliverdin) and also caused an inactivation of heme oxygenase. By taking into account the amount of dioxygen incorporated into hydrogen peroxide and some other factors, it could be deduced that 3 mol of dioxygen is consumed for the formation of 1 mol of biliverdin in the heme oxygenase reaction.

Animals↗
PubMed2005

The lower intestinal tract-specific induction of heme oxygenase-1 by glutamine protects against endotoxemic intestinal injury.

OBJECTIVE: The aim of the present study was to investigate whether glutamine pretreatment improves intestinal injury in rats with endotoxemia by its heme oxygenase-1 induction in the lower intestinal tract. DESIGN: Randomized, blinded, controlled animal study. SETTING: University-based animal research facility. SUBJECTS: Sprague-Dawley male rats, weighing 220-250 g (n = 201). INTERVENTIONS: Rats were treated with glutamine (0.75 g/kg) dissolved in lactated Ringer's solution via the tail vein. Endotoxemia was induced in rats by intraperitoneal injection of lipopolysaccharide (10 mg/kg or 20 mg/kg for survival study). Lipopolysaccharide-treated animals were pretreated with glutamine or lactated Ringer's solution 9 hrs before lipopolysaccharide treatment. Some of the glutamine-pretreated animals further received tin mesoporphyrin (1 micromol/kg), a specific inhibitor of heme oxygenase activity, 1 hr before lipopolysaccharide treatment. MEASUREMENTS AND MAIN RESULTS: Glutamine treatment markedly induced heme oxygenase-1 messenger RNA and protein in the mucosal epithelial cells as well as in the lamina propria cells in the ileum and the colon, whereas its expression in the duodenum and the jejunum was not influenced by the treatment. Glutamine treatment before lipopolysaccharide administration significantly ameliorated lipopolysaccharide-induced mucosal injury, inflammation, and apoptotic cell death in the ileum and the colon, as judged by significant decreases in tumor necrosis factor-alpha gene expression, histologic damage scores, and expression of activated caspase-3 and by an increase in gene expression of Bcl-2. In addition, glutamine treatment markedly decreased lipopolysaccharide-induced mortality. In contrast, treatment with tin mesoporphyrin abolished the beneficial effect of glutamine pretreatment. CONCLUSIONS: Glutamine pretreatment significantly ameliorated intestinal tissue injury of rats following lipopolysaccharide treatment. The same treatment also improved the survival of animals from endotoxemia. The protective effect of glutamine is mediated by its lower intestine-specific induction of heme oxygenase-1, since its inhibition by tin mesoporphyrin completely abolished the beneficial effect of glutamine.

Animals↗
PubMed1997

Development of refractoriness of induced human heme oxygenase-1 gene expression to reinduction by UVA irradiation and hemin.

Using primary human fibroblasts we have observed the existence of an acquired refractoriness of the heme oxygenase-1 gene to induction by a second dose of UVA (320-380 nm) radiation. We studied the kinetics of development of refractoriness over a time interval of up to 72 h between the first inducing event and the second (challenge) dose. Complete refractoriness was observed at 48 h. We also studied development of refractoriness after UVA, sodium arsenite and H2O2 treatment in all possible combinations and demonstrated that only UVA led to refractoriness. Ultraviolet radiation induced partial refractoriness to H2O2 induction but did not change the response to sodium arsenite. In an investigation of the mechanism of development of refractoriness we used the heme oxygenase inhibitor, tin-protoporphyrin IX and showed that induction of heme oxygenase enzymatic activity is a crucial step. However, the induction of ferritin, which is known to play a key role in protection against oxidative stress, did not appear to be involved. Damage to membranes is also probably not involved in the refractoriness mechanism. Because either hemin alone or UVA radiation are able to lead to a refractoriness of the heme oxygenase-1 gene to reinduction by a second exposure to one or the other agent in human fibroblasts, we conclude that heme, or an as yet unidentified heme derivative, is involved in the refractoriness response.

Cell Line↗
PubMed2000

Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction.

Bilirubin is a potent antioxidant generated intracellularly during the degradation of heme by the enzyme heme oxygenase. The purpose of this study was to determine the role of increased cardiac bilirubin in protection against postischemic myocardial dysfunction. Rat hearts were isolated and perfused according to the Langendorff technique to evaluate the recovery of myocardial function after 30 min of global ischemia and 60 min of reperfusion. We found that upregulation of the inducible isoform of heme oxygenase (HO-1) by treatment of animals with hemin 24 h before ischemia ameliorated myocardial function and reduced infarct size (tetrazolium staining) on reperfusion of isolated hearts. Tin protoporphyrin IX, an inhibitor of heme oxygenase activity, completely abolished the improved postischemic myocardial performance observed after hemin-mediated HO-1 induction. Likewise, cardiac tissue injury was exacerbated by treatment with tin protoporphyrin IX. Increased cardiac HO-1 expression and heme oxygenase activity were associated with enhanced tissue bilirubin content and an increased rate of bilirubin release into the perfusion buffer. Furthermore, exogenously administered bilirubin at concentrations as low as 100 nanomolar significantly restored myocardial function and minimized both infarct size and mitochondrial damage on reperfusion. Our data provide strong evidence for a primary role of HO-1-derived bilirubin in cardioprotection against reperfusion injury.

Animals↗
PubMed2001

Role of heme oxygenase-1 in hypoxia-reoxygenation: requirement of substrate heme to promote cardioprotection.

Heme oxygenase-1 (HO-1) catalyzes the enzymatic degradation of heme to carbon monoxide, bilirubin, and iron. All three products possess biological functions; bilirubin, in particular, is a potent free radical scavenger of which its antioxidant property is enhanced at low oxygen tension. Here, we investigated the effect of severe hypoxia and reoxygenation on HO-1 expression in cardiomyocytes and determined whether HO-1 and its product, bilirubin, have a protective role against reoxygenation damage. Hypoxia caused a time-dependent increase in both HO-1 expression and heme oxygenase activity, which gradually declined during reoxygenation. Reoxygenation of hypoxic cardiomyocytes produced marked injury; however, incubation with hemin or bilirubin during hypoxia considerably reduced the damage at reoxygenation. The protective effect of hemin is attributable to increased availability of substrate for heme oxygenase activity, because hypoxic cardiomyocytes generated very little bilirubin when incubated with medium alone but produced substantial bile pigment in the presence of hemin. Interestingly, incubation with hemin also maintained high heme oxygenase activity levels during the reoxygenation period. Reactive oxygen species generation was enhanced after hypoxia, and hemin and bilirubin were capable once again to attenuate this effect. These results indicate that the HO-1-bilirubin pathway can effectively defend hypoxic cardiomyocytes against reoxygenation injury and highlight the issue of heme availability in the cytoprotective action afforded by HO-1.

Animals↗
PubMed1981

The potent heme oxygenase inducing action of arsenic and parasiticidal arsenicals.

The administration of trivalent arsenic, either as sodium arsenite or as the trypanocidal drug melarsoprol, to rats produced a profound induction of microsomal heme oxygenase (EC 1.14.99.3) in both liver and kidney and a concomitant decrease in cytochrome P-450 content. In addition, perturbations of delta-aminolevulinate synthase were observed which showed an initial decline followed by a rebound increase in the activity of this enzyme with arsenical treatment. Pentavalent arsenic did not induce hepatic heme oxygenase but did induce the enzyme in kidney, although to a lesser extent (50%) than trivalent arsenic. Treatment of isolated chick embryo liver cells in vitro with sodium arsenite or the parasiticidal drug melarsoprol also showed a potent induction of heme oxygenase. These findings describe a new and potent ability of arsenic and parasiticidal arsenicals to induce heme oxygenase resulting in enhanced degradation of cellular heme.

Animals↗
PubMed1987

Relationship of suppression of the androgenic axis by cobalt-protoporphyrin to its effects on weight loss and hepatic heme oxygenase induction.

Cobalt-protoporphyrin administration to adult male rats results in an intense induction of hepatic heme oxygenase, a pronounced decline of cytochrome P-450 content in liver and associated metabolic abnormalities, including a dose-dependent decrease in weight gain and a marked decline in serum concentrations of testosterone without a compensatory increase in serum luteinizing hormone levels. These abnormalities persist for at least 5-6 weeks after a single subcutaneous dose of the metalloporphyrin (25 mumol/kg b.w.). Experiments with pair-fed control and metalloporphyrin-treated rats indicated that the androgenic dysfunction produced by cobalt-protoporphyrin is not causally related to the associated weight loss produced by the compound. Hepatic heme oxygenase activity was markedly induced by cobalt-protoporphyrin as expected; the enzyme activity was not altered in hypothalami of treated rats but was elevated (approximately 5-fold) in pooled pituitaries. However, despite the expected decrease in hepatic cytochrome P-450 content, no changes were noted in cytochrome P-450 content of hypothalami or pituitaries. In experiments in which the enhanced heme oxygenase activity produced in liver by cobalt-protoporphyrin was completely antagonized by tin-protoporphyrin, a competitive inhibitor of the enzyme, neither the endocrine suppression nor the weight loss produced by cobalt-protoporphyrin was altered. These phenomena were thus clearly dissociated from the effects of cobalt-protoporphyrin on heme oxygenase. Whether or not cobalt-protoporphyrin acts centrally to impair both appetite and endocrine control mechanisms could not be determined in these experiments, but remains a possible explanation of the novel actions of this synthetic heme analogue.

Androgens↗
PubMed1989

The in vitro and in vivo inhibition of intestinal heme oxygenase by tin-protoporphyrin.

The effects of tin-protoporphyrin (SnPP) on the activity of heme oxygenase in the epithelium of the proximal region of the small intestine were examined in male Sprague-Dawley rats. A single dose of SnPP (25 mumol/kg body weight) administered either parenterally or by gavage-produced time-dependent decreases in the activity of microsomal heme oxygenase over 24-48 h. Although heme oxygenase activity reverted to normal levels within 24 h after oral dosing, parenteral treatment resulted in substantial (70%) inhibition of the enzyme through at least 48 h after administration of the metalloporphyrin. In vitro, SnPP was shown to be a competitive inhibitor of microsomal heme oxygenase (Ki = 0.017 microM). Tissue tin levels were determined by graphite furnace atomic absorption spectroscopy 48 h after SnPP treatments. Comparable levels of tin were found in the liver and kidney after parenteral treatment (14.34 +/- 1.50 and 14.39 +/- 0.45 micrograms/g dry weight, respectively) while only 1.5-3% of these amounts were found in these organs after oral treatment with the metalloporphyrin. These studies establish that the rate-limiting enzyme in the catabolism of heme to bilirubin is inhibited in intestinal epithelium to the same extent as the enzyme is inhibited in other organs.

Animals↗
PubMed2005

Heme oxygenase-1: from bench to bedside.

As aspects of basic science come to play an increasingly prominent role in clinical medicine, heme oxygenase-1 is one of several molecules emerging as a central player in diseases of the lung and intensive care unit. Although the apparent raison d'être of this enzyme is to dispose of heme, its activity results in cytoprotection against oxidative injury and cellular stresses. As the lung interfaces directly with an oxidizing environment, it is expected that heme oxygenase-1 would be involved in many aspects of lung health and disease. The protective effects of heme oxygenase-1 and products of its enzymatic activity, including carbon monoxide, biliverdin and bilirubin, and ferritin, have opened the door to potential therapeutic and disease-monitoring possibilities that one day may be applicable to pulmonary medicine. This article introduces readers to the history of heme oxygenase research, the role of this enzyme in the lung, and related new developments to look forward to in the fields of pulmonary and critical care medicine.

Animals↗