Showing papers on "Heme oxygenase published in 1994"
TL;DR: Data indicate that interaction of AGEs with cellular targets, such as ECs, leads to oxidant stress resulting in changes in gene expression and other cellular properties, potentially contributing to the development of vascular lesions.
1,351 citations
TL;DR: It is shown that human skin fibroblasts, preirradiated with UVA, sustain less membrane damage during a subsequent exposure to UVA radiation than cells that had not been preiradiated.
Abstract: Oxidative stress of human skin fibroblasts by treatment with ultraviolet A (UVA) radiation has been shown to lead to an increase in levels of the heme catabolizing enzyme heme oxygenase 1 [heme, hydrogen-donor:oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating), EC 1.14.99.3] and the iron storage protein ferritin. Here we show that human skin fibroblasts, preirradiated with UVA, sustain less membrane damage during a subsequent exposure to UVA radiation than cells that had not been preirradiated. Pretreating cells with heme oxygenase 1 antisense oligonucleotide inhibited the irradiation-dependent induction of both the heme oxygenase I enzyme and ferritin and abolished the protective effect of preirradiation. Inhibition of the UVA preirradiation-dependent increase in ferritin, but not heme oxygenase, with desferrioxamine also abolished the protection. This identifies heme oxygenase 1 as a crucial enzymatic intermediate in an oxidant stress-inducible antioxidant defense mechanism, involving ferritin, in human skin fibroblasts.
515 citations
Journal Article•
TL;DR: The increase in heme oxygenase-1 protein in association with the neurofibrillary pathology of Alzheimer's disease and other diseases characterized by neurofigrillary tangles supports the notion that the generation of free radicals and oxidative stress plays a role in the pathogenesis of neurofibillary pathology.
Abstract: Heme oxygenase-1 is an important enzyme that degrades heme, a pro-oxidant, leading to the formation of antioxidant molecules. In this study we demonstrate by immunocytochemistry close association of heme oxygenase-1 with Alzheimer neurofibrillary pathology and with the neurofibrillary tangles found in progressive supranuclear palsy and subacute sclerosing panencephalitis. In Alzheimer's disease, using two different rabbit antisera against heme oxygenase-1 protein, we localized, using immunocytochemical methods, heme oxygenase-1 to neurofibrillary tangles, senile plaque neurites, granulovacuolar degeneration, and neuropil threads. Only light background staining was seen in young controls and sporadic lesion-related immunoreactivity in age-matched controls. The increase in heme oxygenase-1 protein in association with the neurofibrillary pathology of Alzheimer's disease and other diseases characterized by neurofibrillary tangles supports the notion that the generation of free radicals and oxidative stress plays a role in the pathogenesis of neurofibrillary pathology.
438 citations
TL;DR: The presence of regulatory sequences for the binding of transcription factors such as NF-kappa B and AP-2, whose activation is associated with the immediate response of the cell to an injury, may be an indication of the important role which HO-1 may play in defense mechanisms against tissue injury.
Abstract: Heme oxygenase (HO) is the rate-limiting enzyme in heme catabolism and its activity is induced by many agents, including its substrate heme, heavy metals, UV radiation, and other injurious oxidant conditions. We examined the presence of several regulatory elements in the promoter region of the human HO-1 gene which could possibly account for its induction in response to diverse agents or influences. Heme treatment increased both HO activity and HO-1 mRNA in the human erythroleukemic cell line K562. Electrophoretic mobility-shift assays of nuclear protein extracts from heme-treated and control cells with specific oligonucleotide probes containing binding sites for known transcription factors, including AP-1, AP-2, Sp1, NF-kappa B, CTF/NF1, TFIID, OKT1, and CREB, and oligonucleotides containing serum-, metal-, and glucocorticoid-responsive elements demonstrated a specific and marked increase in the NF-kappa B and AP-2 transcription factors and, to a lesser extent, an increase in AP-1. No significant increase in other transcription factors over the control, untreated cells was observed. DNase I footprint assays using purified transcription factors revealed the presence of NF-kappa B and AP-2 binding sites in the proximal part of the promoter region of the human HO-1 gene. Moreover, nucleotide sequence analysis of the HO-1 promoter region showed that the protected regions encompassed NF-kappa B and AP-2 consensus binding sites. The presence of regulatory sequences for the binding of transcription factors such as NF-kappa B and AP-2, whose activation is associated with the immediate response of the cell to an injury, may be an indication of the important role which HO-1 may play in defense mechanisms against tissue injury.
415 citations
TL;DR: The proposal that the induction of heme oxygenase by cobalt chloride may be a general response to oxidant stress and, by increasing bilirubin levels, could constitute an important cellular defense mechanism against oxidative damage is supported.
299 citations
TL;DR: Together these data do not support carbon monoxide as a mediator in either LTP induction or expression/maintenance and emphasize further the nonselectivity of some metalloporphyrins.
217 citations
TL;DR: It is shown that CO can function as an endogenous modulator of vascular perfusion in the liver, and zinc protoporphyrin IX promoted an increase in the perfusion pressure under the constant flow conditions.
147 citations
TL;DR: The results suggest that heme oxygenase may play a role in modulating guanylyl cyclase independent of nitric oxide synthase, which may result from regulation of intracellular heme and carbon monoxide levels by the he me oxygenase system.
145 citations
TL;DR: Using the synthetic cadmium-responsive elements containing various base changes, it is suggested that a 10-base pair sequence, TGCTAGATTT, required for the cad mium-mediated inducibility and in vitro protein binding is involved in the cadmum-mediated activation of the heme oxygenase gene.
137 citations
Journal Article•
TL;DR: Examination of the microsomal heme oxygenase system at the transcript, protein and activity levels and response of heart nitric oxide activity and cyclic GMP levels to stress shows the sensitivity of only the HO-1 isozyme to heat stress in these tissues.
Abstract: Presently we have investigated the carbon monoxide generating capacity of the cardiovascular system under normal and stress conditions by examining the microsomal heme oxygenase system at the transcript, protein and activity levels; and have assessed response of heart nitric oxide (NO) synthase activity and cyclic GMP levels to stress. Heme oxygenase (HO) isozymes, HO-1 (HSP32) and HO-2, catalyze the rate limiting step in the only known pathway in eukaryotes for the generation of the potential cellular message, carbon monoxide, and the antioxidant, bilirubin. We show expression of HO-1 and HO-2 at both the transcription and protein levels under normal conditions in the heart and descending aorta, and demonstrate the sensitivity of only the HO-1 isozyme to heat stress in these tissues. The ratio of the two HO-2 homologous transcripts (approximately 1.9 and 1.3 Kb) present in the atrium, ventricles and descending aorta and their levels were not altered by hyperthermia (42 degrees C, 20 min) when measured 1 or 6 hr after treatment. In contrast, hyperthermia caused a rapid, robust and coordinate increase of approximately 10- to 32-fold in the approximately 1.8-Kb HO-1 mRNA in these tissues when measured 1-hr post-treatment. Hyperthermia also caused a significant increase in both HO-1 protein and heme degradation capacity in the heart. Furthermore, the induction of HO-1 protein in the heart was accompanied by a significant elevation in tissue cyclic GMP level first detected 1-hr post-treatment and was sustained 6 hr after heat shock.(ABSTRACT TRUNCATED AT 250 WORDS)
122 citations
TL;DR: It is demonstrated for the first time that heme oxygenase‐1 can be induced by an important cytokine, TGF‐β1, causing an increase in the expression of both HO‐1 message and protein in specific neuroepithelial and fibroblast cells.
Abstract: Antibodies specific for heme oxygenase-1 (HO-1) were produced in rabbits, using the multiple antigen peptide (MAP) technique, and were employed to investigate the ability of transforming growth factor-beta 1 (TGF-beta 1) to induce the HO-1 protein in cultured human retinal pigment epithelial (RPE) cells. Western blot analyses showed that the cytokine induced HO-1 in these cells in a time- and dose-dependent manner. TGF-beta 1 also increased the mRNA for HO-1 in treated cells prior to the increase in HO-1 protein. The induction was effectively blocked by a neutralizing antibody preparation against TGF-beta 1. When tested under similar conditions, other growth factors such as basic fibroblast growth factor-I, platelet-derived growth factor, insulin-like growth factor, transforming growth factor-alpha, and epidermal growth factor did not show appreciable induction of HO-1. Lipopolysaccharide, tumor necrosis factor-alpha, and interferon-gamma were also not inducers, although TGF-beta 2 effectively induced HO-1. Heavy metal ions and thiol reagents were also highly potent inducers of HO-1 in human RPE cells. The induction of HO-1 by TGF-beta 1 was also observed in bovine choroid fibroblasts, but not in HELA, HEL or bovine corneal fibroblasts. Our results demonstrate for the first time that HO-1 can be induced by an important cytokine, TGF-beta 1, causing an increase in the expression of both HO-1 message and protein in specific neuroepithelial and fibroblast cells.
TL;DR: expression of the inducible form of heme oxygenase (HO-1) was investigated in rat brain following 20 min of forebrain ischemia by Northern blot and in situ hybridization analyses, and the level of HO-1 mRNA was undetectable in the cerebral cortex of sham control, but increased following ischemic insult.
TL;DR: The active site of the heme-heme oxygenase complex has a myoglobin-like structure rather than an active site similar to the large cytochrome P-450 class of monooxygenases, in which the activated form is an oxo intermediate.
TL;DR: Polymerase chain reaction and fluorescence in situ hybridization were employed to determine the chromosome localization of the genes coding for the two known heme oxygenase isozymes and it was found that Heme oxygenase-1 (HMOX1), the inducible form, was localized to human chromosome 22q12, while HMOX2, the constitutive form,was localized to chromosome 16p13.
TL;DR: Although the H25A mutant protein shows no heme oxygenase activity, the heme is competent to bind carbon monoxide, and this ferrous heme-H25A HO complex exists as an equilibrium mixture between a five-coordinate, high-spin species and a four-coordinated, intermediate- spin species.
Abstract: Electronic and resonance Raman spectroscopic studies are reported for the His25Ala mutant of human liver heme oxygenase (HO) and its complex with heme. In the oxidized (ferric) form of the enzyme.substrate complex, the heme is shown to be in a high-spin, five-coordinate state. This is distinct from the same complex in the wild-type enzyme in which the heme is six-coordinate, ligated to a proximal histidine and a water molecule in an environment reminiscent of aquometmyoglobin. The reduced (ferrous) form of the complex of the H25A heme oxygenase mutant has lost the very prominent resonance Raman band at approximately 217 cm-1 seen in the wild-type complex that has been unambiguously assigned to the proximal Fe-N(His) vibrational frequency [Sun et al. (1993) Biochemistry 32, 14151; Takahashi et al. (1994) Biochemistry 33, 1010]. The absence of this band in the spectrum of the mutant protein definitively identifies His 25 as the proximal ligand of the heme substrate. Furthermore, this ferrous heme-H25A HO complex exists as an equilibrium mixture between a five-coordinate, high-spin species and a four-coordinate, intermediate-spin species. Although the H25A mutant protein shows no heme oxygenase activity, the heme is competent to bind carbon monoxide. Studies of the CO adduct of the H25A HO complex show v(CO) and v(Fe-CO) frequencies at 1960 and 529 cm-1, respectively, that are characteristic of a hydrophobic carbon monoxide binding site on a heme with a weak proximal ligand.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The results rule out a nucleophilic mechanism for the alpha-meso-hydroxylation catalyzed by heme oxygenase and indicate that it involves electrophilic addition of the distal oxygen of iron-bound peroxide (FeIII-OOH) to the porphyrin ring.
TL;DR: Findings provide evidence that endogenous CO may play a role in the control of CRH release; by analogy with NO, CO may represent a major new neuroendocrine modulator.
Abstract: Although recent evidence suggests that the gas nitric oxide (NO) can modulate the secretion of corticotropin-releasing hormone (CRH) from acute rat hypothalamic explants, another gas, carbon monoxide (CO), has been suggested to play a role in neural signaling in the brain; CO may complement the activity of NO in long term potentiation. In this study, we have investigated whether CO shares with NO the ability to modify the release of CRH from the rat hypothalamus. Hemin, a specific CO precursor through the enzyme heme oxygenase (the enzymatic pathway synthesizing endogenous CO), was found to inhibit in a dose-dependent manner KCl-stimulated CRH release, with a maximal effect at 1 microM, while showing no effect on basal CRH secretion. The stimulation of CRH by interleukin-1 beta (100 ng/ml) was also significantly antagonized by hemin (1 microM). An inhibitor of heme oxygenase, zinc-protoporphyrin-9, had no effect on basal or stimulated CRH release up to a maximal dose of 10 microM. When hemin and zinc-protoporphyrin-9 were given together, the hemin-induced inhibition of CRH release was completely antagonized by the enzyme inhibitor. These findings provide evidence that endogenous CO may play a role in the control of CRH release; by analogy with NO, CO may represent a major new neuroendocrine modulator.
TL;DR: It is shown that heme catalyzes the oxidation of low density lipoproteins which can damage vascular endothelial cells and paradoxically, more prolonged exposure of endothelium to heme or methemoglobin renders them remarkably resistant to oxidant challenge.
Abstract: Heme proteins transport oxygen and facilitate redox reactions. Heme, however, may be dangerous, especially when free in biologic systems. For example, iron released from hemoglobin-derived heme can catalyze oxidative injury to neuronal cell membranes and may be a factor in post-traumatic damage to the central nervous system. We have shown that heme catalyzes the oxidation of low density lipoproteins which can damage vascular endothelial cells. The endothelium is susceptible to damage by oxidants generated by activated phagocytes, and this has been invoked as an important mechanism in a number of pathologies including the Adulte Respiratory Distress Syndrome (ARDS), acute tubular necrosis, reperfusion injury and atherosclerosis. Because of its highly hydrophobic nature, heme readily intercalates into endothelial membranes and potentiates oxidant-mediated damage. This injury is dependent on the iron content of heme and is completely blocked when concomitant hemopexin is added. Ferrohemoglobin, when added to cultured endothelial cells, is without deleterious effects, but if oxidized to ferrihemoglobin (methemoglobin), it greatly amplifies oxidant damage. Methemoglobin, but not ferrohemoglobin, releases its hemes which can then be incorporated into endothelial cells. Cultured endothelial cells, when exposed to methemoglobin but not ferrohemoglobin, cytochrome c or metmyoglobin, potentiate this oxidant injury. Stabilization of the methemoglobin by cyanide, haptoglobin or capture of the heme by hemopexin abrogates this effect. Paradoxically, more prolonged exposure of endothelium to heme or methemoglobin renders them remarkably resistant to oxidant challenge. Endothelium defends itself from heme by induction of the heme degrading enzyme heme oxygenase and the concomitant production of large amounts of the iron binding protein ferritin.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal Article•
TL;DR: Evidence suggests that in the central nervous system cellular CO production can influence cGMP levels through effects on soluble guanylyl cyclase activity, and may be important in the cell's response to environmental changes.
TL;DR: Human fibroblasts were 10-fold more susceptible than Chinese hamster ovary cells to sodium arsenite, and arsenic-resistant cells were established from CHO cells and from a human lung adenocarcinoma cell line (CL3).
Abstract: Human fibroblasts (HFW) were 10-fold more susceptible than Chinese hamster ovary (CHO-K1) cells to sodium arsenite. Comparison of cellular antioxidant enzyme activities showed that CHO-K1 cells contained 3- and 8-fold more glutathione-peroxidase and catalase activities, respectively, than HFW cells. Since vitamin E, methylamine, and benzyl alcohol could prevent, in part, the arsenite-induced killing of HFW cells, we suggest that arsenite can induce oxidative damage in HFW cells. We have also established arsenic-resistant cells, SA7 and CL3R, from CHO cells and from a human lung adenocarcinoma cell line (CL3), respectively. The arsenic resistance of SA7 cells was attributed mainly to elevation of glutathione S-transferase pi levels, and that of CL3R cells was possibly due to an increase in heme oxygenase activity. Since induction of heme oxygenase is a general response to oxidative stress, we suspect that the differential toxicity of arsenic to human and animal cells could be due to arsenic's more efficient induction of oxidative damage in human cells.
TL;DR: The resonance Raman spectra of ferric and ferrous forms of the heme-heme oxygenase (HO) complex (isoform 1) clarify several structural features of the catalytic active site and indicate that the neutral imidazole may play several important roles in the physiological function of theheme-HO complex.
Abstract: The resonance Raman spectra of ferric and ferrous forms of the heme-heme oxygenase (HO) complex (isoform 1) clarify several structural features of the catalytic active site. Isotopic substitution studies of the central iron atom of the heme demonstrate that the line at 218 cm-1 in the ferrous ligand-free form of the complex originates from the iron-histidine stretching mode. The presence of a Raman line at this frequency confirms that the fifth ligand coordinating to the heme is a neutral imidazole from a histidine residue. The modes associated with CO in the carboxy derivative of the ferrous enzyme complex have typical frequencies of histidine-bound heme proteins such as myoglobin. In the ferric form of the complex, at alkaline pH, hydroxide is identified as the bound exogenous ligand, and at neutral pH we infer that water is bound. Thus, the coordination of the heme-HO complex is the same as that in myoglobin. However, in a comparison of the low-frequency vibrational modes in the resonance Raman spectrum of the heme-HO complex to those of myoglobin, the spectra are found to be very different, indicating that the interactions between the heme and its amino acid pocket in these two proteins are quite different. The neutral imidazole may play several important roles in the physiological function of the heme-HO complex.
TL;DR: It is suggested that the induction of heme oxygenase by heat stress is a physiologically relevant defense mechanism whereby both the degradation of heMe of denatured hemoproteins and the generation of biologically active products of heME catabolism are enhanced.
TL;DR: Heme oxygenase (HO-1) gene expression was studied in the brains of rats subjected to 30 min global cerebral ischemia followed by recirculation of up to 24 h, and it was found that, when PCR reactions were run for 22 cycles, the amount of PCR products correlated closely with the amounts of cDNA.
TL;DR: This chapter describes two major regulatory pathways—namely, the oxyR and soxR systems, which regulates nine genes induced by hydrogen peroxide in both Escherichia coli and Salmonella typhimurium and appears to be a fairly sensitive marker of oxidative stress.
Abstract: Publisher Summary Bacteria respond to oxidative stress by the rapid and transient expression of a large number of genes. This chapter describes two major regulatory pathways—namely, the oxyR and soxR systems. The oxyR system regulates nine genes induced by hydrogen peroxide in both Escherichia coli and Salmonella typhimurium. Several oxyR-controlled genes (for example, catalase, glutathione reductase, and alkyl hydroperoxide reductase) play a role in defense against oxidative stress. The detection of expression of the oxyR regulon and the soxR regulon provides an early marker of oxidative stress in prokaryotes. The binding of several eukaryotic transcription factors, such as NF-кB and the fos–jun heterodimer (AP-1) may be redox regulated. Expression of the c-jun oncogene is stimulated by either UVC radiation (254 nm) or hydrogen peroxide. On the other hand, expression of the human heme oxygenase 1 (HO-1) gene is not induced by UVC radiation, whereas it is strongly induced by oxidizing agents such as UVA (320–380 nm) radiation or hydrogen peroxide. Additionally, the gene is induced by other agents, such as phorbol esters, heavy metals, and sodium arsenite. Although this phenomenon was originally observed in fibroblasts cultured from human skin, induction occurs in most human cell types and all mammalian cell types so far tested. The induction is clearly related to the cellular redox state because lowering cellular glutathione levels strongly enhances HO-1 mRNA accumulation). For these reasons, altered expression of the HO-1 gene appears to be a fairly sensitive marker of oxidative stress.
TL;DR: The effects of interleukin-6, the major inducer of the acute-phase reaction, on the expression of cytochrome P450IA1 (CYPIA1) were examined using human HepG2 hepatoma cells, suggesting that the suppressive effect of IL-6 on CYPIA1 mRNA may be due to a loss of heme.
TL;DR: It is concluded that SnCl2 induces activation of the HO-1 gene, which is followed by elevation in enzyme activity and a decrease in cytochrome P450-arachidonic acid ω-hydroxylase activity, which brings about a selective decrease in the synthesis of 19-HETE and 20- HETE, arachidonate metabolites with prohypertensive properties, and are associated with blood pressure reduction to normal levels.
TL;DR: The results suggest that hyporesponsiveness to NE caused by LPS is due to the activation of soluble guanylyl cyclase, which is partially mediated by N(O), but not by CO, and LPS may induce the production of another mediator(s) that activate soluble GuanylyL cyclase in the vascular smooth muscle.
TL;DR: It is suggested that carbon monoxide plays a pivotal role in glutamate release in synapses, and may be a retrograde messenger in long-term potentiation.
TL;DR: Neither catalase nor the iron cation chelating agent o-phenanthroline were able to suppress or even to reduce HO expression in smoke-bubbled PBS-treated cells, and at comparable concentrations both compounds were found to be potent inhibitors of smoke-dependent DNA strand breaks.
Abstract: A dose-dependent and transiently elevated expression of a cytoplasmic 32 kDa protein was observed in Swiss albino 3T3 fibroblasts exposed to mainstream cigarette smoke (CS) trapped in phosphate-buffered saline solutions (smoke-bubbled PBS). The protein was identified as heme oxygenase (HO) (heme, hydrogen donor:oxygen oxidoreductase, EC 1.14.99.3) by Western blotting using an anti-rodent HO-specific antibody. Kinetic investigations revealed that HO protein and its mRNA were detectable in smoke-bubbled PBS-treated cells between 1 and 24 h after exposure to 0.03 puffs (approximately 1 cm3) CS per ml medium. As a result of transcriptional activation, a nearly 50-fold increase in the amount of HO mRNA was determined after 8 h exposure compared to control levels. Since literature data indicate that there is a link between glutathione depletion and HO expression, the same was assumed for cells exposed to smoke-bubbled PBS, as a decrease of more than 60% in glutathione levels was observed after the exposure. This was further supported by the observation that no elevated amounts of HO mRNA appeared in smoke-bubbled PBS-treated cells when cysteine was exogenously added. However, although these effects may be attributable to the formation of hydroxyl radicals (which have been shown to induce HO and to deplete glutathione levels and which appear in aqueous smoke-containing solutions via the iron-catalysed Fenton reaction) neither catalase nor the iron cation chelating agent o-phenanthroline were able to suppress or even to reduce HO expression in smoke-bubbled PBS-treated cells. On the contrary, at comparable concentrations both compounds were found to be potent inhibitors of smoke-dependent DNA strand breaks. Hence, reactive species other than Fenton reaction-derived hydroxyl radicals are responsible for the effects observed in the present study.
TL;DR: It is indicated that cAMP has a direct enhancing effect on the expression of stress proteins controlled by a classic heat‐shock promoter, while decreasing their expression when induced by oxidative stress.
Abstract: The synthesis of heat-shock proteins (HSPs) and other stress proteins, including heme oxygenase (HO) and ferritin, is differentially induced by heat and oxidizing agents. In order to determine what role cAMP plays in those inductions in human monocytes-macrophages (mϕ), we used cAMP activators or analogues alone or in combination with various stressful conditions. A stimulation in cAMP production did not per se affect stress proteins synthesis in mϕ but modulated their induction in a differential way according to the stimulus. cAMP increased the synthesis of HSPs after heat shock. During erythrophagocytosis, whereas cAMP depressed the phagocytic process and the associated generation of superoxide anions, it enhanced the synthesis of HSPs, while inhibiting that of HO and ferritin. These results indicate that cAMP has a direct enhancing effect on the expression of stress proteins controlled by a classic heat-shock promoter, while decreasing their expression when induced by oxidative stress. © 1994 Wiley-Liss, Inc.