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PubMed2003

The oxygenase component of phenol hydroxylase from Acinetobacter radioresistens S13.

Phenol hydroxylase (PH) from Acinetobacter radioresistens S13 represents an example of multicomponent aromatic ring monooxygenase made up of three moieties: a reductase (PHR), an oxygenase (PHO) and a regulative component (PHI). The function of the oxygenase component (PHO), here characterized for the first time, is to bind molecular oxygen and catalyse the mono-hydroxylation of substrates (phenol, and with less efficiency, chloro- and methyl-phenol and naphthol). PHO was purified from extracts of A. radioresistens S13 cells and shown to be a dimer of 206 kDa. Each monomer is composed by three subunits: alpha (54 kDa), beta (38 kDa) and gamma (11 kDa). The gene encoding PHO alpha (named mopN) was cloned and sequenced and the corresponding amino acid sequence matched with that of functionally related oxygenases. By structural alignment with the catalytic subunits of methane monooxygenase (MMO) and alkene monooxygenase, we propose that PHO alpha contains the enzyme active site, harbouring a dinuclear iron centre Fe-O-Fe, as also suggested by spectral analysis. Conserved hydrophobic amino acids known to define the substrate recognition pocket, are also present in the alpha-subunit. The prevalence of alpha-helices (99.6%) as studied by CD confirmed the hypothized structural homologies between PHO and MMO. Three parameters (optimum ionic strength, temperature and pH) that affect kinetics of the overall phenol hydroxylase reaction were further analyzed with a fixed optimal PHR/PHI/PHO ratio of 2/1/1. The highest level of activity was evaluated between 0.075 and 0.1 m of ionic strength, the temperature dependence showed a maximum of activity at 24 degrees C and finally the pH for optimal activity was determined to be 7.5.

Acinetobacter↗
PubMed1999

alpha-oxidation of fatty acids in higher plants. Identification of a pathogen-inducible oxygenase (piox) as an alpha-dioxygenase and biosynthesis of 2-hydroperoxylinolenic acid.

A pathogen-inducible oxygenase in tobacco leaves and a homologous enzyme from Arabidopsis were recently characterized (Sanz, A., Moreno, J. I., and Castresana, C. (1998) Plant Cell 10, 1523-1537). Linolenic acid incubated at 23 degrees C with preparations containing the recombinant enzymes underwent alpha-oxidation with the formation of a chain-shortened aldehyde, i.e., 8(Z),11(Z), 14(Z)-heptadecatrienal (83%), an alpha-hydroxy acid, 2(R)-hydroxy-9(Z),12(Z),15(Z)-octadecatrienoic acid (15%), and a chain-shortened fatty acid, 8(Z),11(Z),14(Z)-heptadecatrienoic acid (2%). When incubations were performed at 0 degrees C, 2(R)-hydroperoxy-9(Z),12(Z),15(Z)-octadecatrienoic acid was obtained as the main product. An intermediary role of 2(R)-hydroperoxy-9(Z), 12(Z),15(Z)-octadecatrienoic acid in alpha-oxidation was demonstrated by re-incubation experiments, in which the hydroperoxide was converted into the same alpha-oxidation products as those formed from linolenic acid. 2(R)-Hydroperoxy-9(Z),12(Z), 15(Z)-octadecatrienoic acid was chemically unstable and had a half-life time in buffer of about 30 min at 23 degrees C. Extracts of cells expressing the recombinant oxygenases accelerated breakdown of the hydroperoxide (half-life time, about 3 min at 23 degrees C), however, this was not attributable to the recombinant enzymes since the same rate of hydroperoxide degradation was observed in the presence of control cells not expressing the enzymes. No significant discrimination between enantiomers was observed in the degradation of 2(R,S)-hydroperoxy-9(Z)-octadecenoic acid in the presence of recombinant oxygenases. A previously studied system for alpha-oxidation in cucumber was re-examined using the newly developed techniques and was found to catalyze the same conversions as those observed with the recombinant enzymes, i.e. enzymatic alpha-dioxygenation of fatty acids into 2(R)-hydroperoxides and a first order, non-stereoselective degradation of hydroperoxides into alpha-oxidation products. It was concluded that the recombinant enzymes from tobacco and Arabidopsis were both alpha-dioxygenases, and that members of this new class of enzymes catalyze the first step of alpha-oxidation in plant tissue.

Aldehydes↗
PubMed2000

Overexpression of heme oxygenase in neuronal cells, the possible interaction with Tau.

Increased expression of heme oxygenase-1 (HO-1) is a common feature in a number of neurodegenerative diseases. Interestingly, the spatial distribution of HO-1 expression in diseased brain is essentially identical to that of pathological expression of tau. In this study, we explored the relationship between HO-1 and tau, using neuroblastoma cells stably transfected with sense and antisense HO-1 constructs as well as with the vector alone. In transfected cells overexpressing HO-1, the activity of heme oxygenase was increased, and conversely, the level of tau protein was dramatically decreased when compared with antisense HO-1 or CEP transfected cells. The suppression of tau protein expression was almost completely reversed by zinc-deuteroporphyrin, a specific inhibitor of heme oxygenase activity. The activated forms of ERKs (extracellular signal-regulated kinases) were also decreased in cells overexpressing HO-1 although no changes in the expression of total ERK-1/2 proteins were observed. These data are in agreement with the finding that the expression of tau is regulated through signal cascades including the ERKs, whose activities are modulated by oxidative stresses. The expression of tau and HO-1 may be regulated by oxidative stresses in a coordinated manner and play a pivotal role in the cytoprotection of neuronal cells.

Alzheimer Disease↗
PubMed1997

Diminished heme oxygenase-1 mRNA expression in RPE cells from diabetic donors as quantitated by competitive RT/PCR.

PURPOSE: The RPE is essential in the maintenance of retinal vasculature homeostasis, since increased cellular expression of heme oxygenase-1 (HO-1) has been implicated as a defense mechanism against oxidative stress. This study was done in an effort to determine the levels of the stress protein (32 kD), HO-1, in retinal pigment epithelium (RPE) cells obtained from diabetic and normal eyes. METHODS: We measured the levels of HO-1 in the RPE from eight normal and six diabetic donor eyes. For comparison, HO-1 levels were assayed in RPE cells from four donor eyes with long-standing hypertension. Heme oxygenase-1 mRNA copy number was determined by competitive RT/PCR on various ex vivo samples and on RPE cultured from the same donors. Total RNA (1-200 ng) was reverse-transcribed and then amplified by PCR in the same tube as an internal standard obtained by deleting a 50 bp restriction site from the native HO-1 gene. RESULTS: Relative to the RPE obtained from control donor eyes, RPE from diabetic donors exhibited significantly decreased levels of HO-1 mRNA. In contrast, no significant difference in the levels of HO-1 mRNA was observed in RPE samples derived from hypertensive donor eyes. The diabetic group showed a range of 340-450 HO-1 mRNA copies/ng of total RNA, as compared to 425-8,000 HO-1 mRNA copies/ng of total RNA in RPE from normal donors and 460-7605 copies/ ng in hypertensive donor eyes. CONCLUSIONS: This study represents initial studies exploring the quantitative expression of heme oxygenase in the RPE human eyes. The decreased expression of HO-1, a stress/heat shock protein, may in the RPE contribute to the vulnerability of the neuroretina to significant metabolic alterations encountered in the diabetic state. This was a limited study; additional screening from different donor eyes will be done in order to establish the relationship between RPE, HO-1 expression and eye diseases in which oxidative stress is believed to be a determinant in the pathophysiology.

Diabetes Mellitus↗
PubMed1999

Redox regulation and oxidant activation of heme oxygenase-1.

The ultraviolet A (UVA, 320-400 nm) component of sunlight has the potential to generate an oxidative stress in cells and tissue so that antioxidants (both endogenous and exogenous) strongly influence the biological effects of UVA. The expression of several genes (including heme oxygenase-1, HO-1; collagenase; the CL100 phosphatase and the nuclear oncogenes, c-fos and c-jun) is induced following physiological doses of UVA to cells and this effect can be strongly enhanced by removing intracellular glutathione or enhancing singlet oxygen lifetime. We have observed that heme is released from microsomal heme-containing proteins by UVA and other oxidants and that activation of HO-1 expression by UVA correlates with levels of heme release. UVA radiation also leads to an increase in labile iron pools (either directly or via HO-1) and eventual increases in ferritin levels. The role of heme oxygenase in protection of skin fibroblasts is probably an emergency inducible defense pathway to remove heme liberated by oxidants. The slower increase in ferritin levels is an adaptive response which serves to keep labile iron pools low and thereby reduce Fenton chemistry and oxidant-induced chain reactions involving lipid peroxidation. In keratinocytes, the primary target of UVA radiation, heme oxygenase levels are constitutively high (because of HO-2 expression). Since there is a corresponding increase in basal levels of ferritin the epidermis appears to be well protected constitutively against the oxidative stress generated by UVA.

Animals↗
PubMed1998

Heme oxygenase-1 induction in skeletal muscle cells: hemin and sodium nitroprusside are regulators in vitro.

The heat shock protein heme oxygenase-1 (HO-1) is regulated by a variety of physiological and pharmacological factors. In skeletal muscle tissue, HO-1 has been shown to be induced only by exercise and electrical stimulation in vivo. Both hemin and sodium nitroprusside (SNP) are potent inducers of HO-1 in other tissues. In this study, we examined the effects of these two agents on HO-1 induction in L6.G8 rat skeletal myoblast cells. Hemin and SNP increased cellular heme oxygenase activity in both a time- and concentration-dependent manner. Increases in the HO-1 mRNA level and protein expression accompanied changes in heme oxygenase activity. The ability of SNP to induce HO-1 in L6.G8 cells was reduced by coincubation with hydroxocobalamin, a known nitric oxide (NO) scavenger, suggesting that NO itself may be involved in HO-1 gene stimulation. These results indicate that HO-1 expression is sensitive to both hemin and SNP in skeletal myoblast cells and may indicate an important regulatory mechanism of heme catabolism in skeletal muscle tissue.

Animals↗
PubMed1998

Localization of heme oxygenase-2 immunoreactivity to parasympathetic ganglia of human and guinea-pig airways.

Carbon monoxide (CO), an activator of soluble guanylate cyclase and generated enzymatically by heme oxygenase-2 (HO-2), is thought to function as an intra- and intercellular neurotransmitter in the central and peripheral nervous system. In the present study, the distribution of HO-2 in airway nerves from both humans and guinea pigs was assessed. HO-2 was found in all neuronal perikarya of the intrinsic ganglia of guinea-pig airways and in all ganglion nerve cell bodies localized to the trachea and bronchi of humans. By contrast, nerve fibers innervating the smooth muscle, lamina propria, and epithelium of the airways in both species were devoid of HO-2 immunoreactivity. HO-1, the inducible isoform of heme oxygenase, was not found in airway nerves. The pattern of distribution of HO-2 observed suggests that CO might serve as a modulator of synaptic neurotransmission in the lung and airways rather than as a bona fide neurotransmitter in the smooth muscle, vasculature, or glands. Consistent with this hypothesis, 8-bromo-cyclic guanosine monophosphate (cGMP) (30 microM), a stable, pharmacologically active analog of cGMP, markedly inhibited vagally-mediated cholinergic contractions of the isolated guinea-pig trachea. In subsequent studies, however, neither inhibiting heme oxygenase with zinc protoporphyrin-IX (30 microM) nor inhibiting the soluble isoform of guanylate cyclase with ODQ (3 microM) had measurable effects on vagally-mediated cholinergic contractions of the trachea. These results indicate that CO could play a modulatory role in efferent (parasympathetic) synaptic neurotransmission in the airways, but under normal conditions may not be activated to an appreciable extent during periods of elevated vagal activity.

Animals↗
PubMed2004

Peroxynitrite-mediated inactivation of heme oxygenases.

BACKGROUND: Endogenous nitric oxide (NO) and carbon monoxide (CO) are generated by nitric oxide synthase and heme oxygenase, respectively. Like NO, CO has been accepted as an important cellular signaling molecule in biological systems. An up-regulation in both gene and protein expression of heme oxygenase-1 (HO-1) under oxidative/nitrosative stress has been well documented, and the protective role of HO-1 and HO-2 against oxidative damage is proposed. However, data on the direct effect of reactive oxygen/nitrogen species (ROS/RNS) on HO function is incomplete. Using gas chromatography to quantify carbon monoxide (CO) formation from heme oxidation, we investigated the effects of peroxynitrite (ONOO-) on the in vitro catalytic activity of rat spleen (HO-1) and brain (HO-2) microsomal heme oxygenases. RESULTS: Exposure to ONOO- led to concentration-dependent but reversible decreases in the activity of microsomal rat spleen and brain HO activity. Spleen HO activity was 100-fold more sensitive to ONOO--dependent inactivation compared to that of the brain, with IC50 values of 0.015 +/- 0.005 mM and 1.25 +/- 0.25 mM respectively. Inhibition of both rat spleen and brain microsomal HO activity was also observed with tetra-nitromethane, a tyrosine nitrating agent, as well as two NO donors, S-nitrosoglutathione (GSNO) and diethylamine NONOate (DEA-NONOate). However, no additive effect was found following the application of NO donors and ONOO- together. CONCLUSION: These results indicate that ONOO- may regulate HO-1 and HO-2 activities by mechanisms that involve different interactions with these proteins. It is suggested that while nitration of tyrosine residues and oxidation of sulfhydryl groups may be involved, consideration should be given to other facets of ONOO- chemistry. This inhibition of HO activity offers a mechanism for cross talk between the nitric oxide synthase and HO systems.

Animals↗
PubMed2003

Neonatal hyperbilirubinemia in Japanese neonates: analysis of the heme oxygenase-1 gene and fetal hemoglobin composition in cord blood.

Neonatal hyperbilirubinemia is frequent and severe in Japanese infants. Although the G71R mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene is associated with severe neonatal hyperbilirubinemia in this population, it accounts for only half of the neonates with severe hyperbilirubinemia. It was suggested that increased bilirubin production would also be associated with severe neonatal hyperbilirubinemia in Japanese infants. To elucidate the genetic factors causing severe hyperbilirubinemia in these patients, we studied two notable factors associated with bilirubin production: heme oxygenase-1, a key enzyme of heme metabolism, and fetal Hb composition, a factor possibly associated with heme load in neonates. We first determined the sequences of promoter and all coding regions of the heme oxygenase-1 gene in Japanese neonates who had undergone phototherapy, but found no mutation except for the polymorphic (GT)n repeats in the promoter region. These repeats modulate the transcription of the heme oxygenase-1 gene, and the longer repeat sequences are known to reduce the transcription. We detected a significant difference in the allele frequencies of each number of (GT)n repeats between Japanese and German populations. However, we could not find a relation between those polymorphisms and neonatal hyperbilirubinemia. We next analyzed the state of Hb switching of the gamma- to beta-globin chain and the phenotype of gamma-globin chain isoforms in cord blood. We found no relation between fetal Hb composition and neonatal hyperbilirubinemia. Further studies are required to elucidate genetic or environmental factors in neonatal hyperbilirubinemia in Japanese infants.

Chromatography, High Pressure Liquid↗
PubMed2001

Estrogen increases endothelial carbon monoxide, heme oxygenase 2, and carbon monoxide-derived cGMP by a receptor-mediated system.

Carbon monoxide, a gaseous activator of soluble guanylyl cyclase formed by a subtype of the enzyme heme oxygenase designated heme oxygenase-2 in vascular endothelium, has been found to dilate blood vessels independently from nitric oxide. Because of the parallels between nitric oxide and carbon monoxide, we speculated that estrogen might affect carbon monoxide production in vascular endothelium. Endothelial cells of human origin (umbilical vein and uterine artery) were incubated for 4 or 24 h with 10(-12)-10(-6) M 17beta-estradiol. 17beta-Estradiol, at a concentration such as that attained during the ovulatory phase of the menstrual cycle (10(-10) M), administrated for 4 h led to a 2-fold increase in intracellular carbon monoxide production and heme oxygenase-2 protein levels (P < 0.05). A reporter assay, measuring the formation of cGMP as the direct product of carbon monoxide-induced activation of soluble guanylyl cyclase in endothelial cells, also revealed a 56% increase in cellular cGMP after treatment with 10(-10) M E2 17beta-estradiol (P < 0.05). By contrast, higher 17beta-estradiol concentrations had no significant respective effects due to nitric oxide synthase inhibition of carbon monoxide release. This 17beta-estradiol effect appeared to be ER dependent, as preincubation with tamoxifen (10(-6) M) blocked the stimulatory effect of 17beta-estradiol in each instance. Our preliminary data indicate a potential role for carbon monoxide as a biological messenger molecule in estrogen-mediated regulation of vascular tone.

Arteries↗
PubMed1981

Effects of age and sex on microsomal heme oxygenase and cytochrome P-450 content in liver of rats.

Effects of age and sex on microsomal heme oxygenase activity and cytochrome P-450 content were investigated in Wister rats. Heme oxygenase activity declined with an increase in age, namely, its activity in 100 days old (young) rats was 58% in male and 72% in female rats as compared with respective 30 days old (immature) rats, and in 300 days old (old) rats it was 32% in male and 39% in female rats. In male rats, cytochrome P-450 content based on 100 g body weight decreased only in old rats as compared with immature rats, whereas a significant reduction was observed in female rats in the content based on mg microsomal protein as well as based on 100 g body weight in young and old animals. In littermate rats at the age of 56 days which obtained by in breeding in our laboratory, sex difference was apparent in heme oxygenase activity and cytochrome P-450 content, and further a good reciprocal correlation between that activity and content (r = 0.9730 in male, and r = -0.852 in female) was observed.

Age Factors↗
PubMed1984

Alterations of hepatic delta-aminolevulinic acid synthetase, heme oxygenase, microsomal cytochrome content and drug metabolism in rats bearing ascitic tumors AH 13, AH 66 and AH 414 and a 3-methylcholanthrene induced tumor.

Hepatic microsomal drug-metabolizing enzyme activities, cytochrome content, delta-aminolevulinic acid (ALA) synthetase and heme oxygenase activities were studied in rats bearing ascitic tumors AH 13, AH 66 and AH 414 and a primary, 3-methylcholanthrene (3-MC)-induced, tumor. Hepatic microsomal drug-metabolizing enzyme activities and cytochrome content were decreased in rats transplanted intraperitoneally with 1-2 x 10(6) cells of ascitic tumor cell lines AH 13, AH 66 and AH 414. The extent of the decrease of the microsomal cytochrome content and enzyme activities were dependent on the tumor-bearing periods after inoculation. Hepatic microsomal heme oxygenase activity was significantly increased concurrently with the decrease of microsomal drug-metabolizing enzyme activities and cytochrome content. Hepatic ALA synthetase was not changed appreciably in these tumor-bearing rats. Similar alterations of microsomal enzyme content and activities were observed in the livers of rats transplanted subcutaneously with AH 66 tumor cells and in rats bearing a primary tumor initiated by the subcutaneous injection of 3-MC. When the tumor was surgically removed from the rats bearing AH 66 subcutaneously, these hepatic microsomal parameters returned to normal levels. Microsomal drug-metabolizing enzyme activities and cytochrome content in these ascitic tumor cells were found to be at very low levels. From these results, if appears that there is an inverse relationship between the increase of microsomal heme oxygenase activity and the decrease of cytochrome P-450 and b5 as well as drug-metabolizing enzymes in the liver of tumor bearing rats.

5-Aminolevulinate Synthetase↗
PubMed1980

Activity of microsomal heme oxygenase in liver and spleen of ascorbic acid-deficient guinea pigs.

Hepatic heme oxygenase activity was significantly altered in vitamin C-deficient guinea pigs. It was increased two-fold after 14 days and was decreased by 20% after 21 days of deprivation of the vitamin (always in comparison with the control value). The apparent Km of the enzyme was also altered in the course of ascorbic acid deficiency. The data of hepatic heme oxygenase activity correspond to previous results on the metabolism of hepatic cytochrome P-450 in different stages of ascorbic acid deprivation. Splenic heme oxygenase activity decreased progressively arriving at 50% of the control value after 21 days of vitamin C omission, its apparent Km remained unaltered.

Animals↗
PubMed1985

Selective inhibitory interactions of alkoxymethylenedioxybenzenes towards mono-oxygenase activity in rat-hepatic microsomes.

A series of eight 4-n-alkoxymethylenedioxybenzene (AMDB) derivatives were evaluated for their inhibitory effects on several mono-oxygenase reactions and their capacity to form metabolite complexes with cytochrome P-450 in vitro in hepatic microsomes from phenobarbital (PB)-and Beta-naphthoflavone (Beta NF)-induced rats. Ethoxyresorufin O-deethylase in Beta NF-induced microsomes and aminopyrine N-demethylase in PB-induced microsomes were most susceptible to inhibition by the test compounds. In contrast, aldrin epoxidation and arylhydrocarbon hydroxylase in PB-and Beta NF-induced microsomes, respectively, were not inhibited by derivatives of AMDB. All AMDB derivatives elicited spectral complexes with cytochrome P-450, the characteristics of which were influenced by the microsomes employed and by the length of the AMDB alkoxy side-chain. Derivatives containing short-chain alkoxy substituents (C1 to C3) formed unstable metabolite complexes and generated substantial quantities of carbon monoxide (CO), those with intermediate length alkoxy groups (C4 to C6) generated little CO and rapidly formed intense spectral complexes (large delta A max), and those with the largest alkoxy groups (C7 and C8) formed no CO and elicited complexes of high stability. Quantitative structure-activity analyses showed that the biological data could be described by parabolic equations in II, the hydrophobic constant of the alkoxy substituent, and suggested the importance to AMDB interactions of a lipophilic-binding region at the active centre of the cytochrome P-450. The alkoxy chain length for optimal mono-oxygenase inhibition and complex formation with cytochrome P-450 appeared to be about five or six carbon atoms. The data suggest that the capacity of AMDB compounds to form stable inhibitory complexes with cytochrome P-450 may not always be associated with their ability to inhibit mono-oxygenase activity.

Aminopyrine N-Demethylase↗
PubMed2000

Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress.

The inducible isoform of haem oxygenase (HO-1) has been proposed as an effective system to counteract oxidant-induced cell injury. In several circumstances, this cytoprotective effect has been attributed to increased generation of the antioxidant bilirubin during haem degradation by HO-1. However, a direct implication for HO-1-derived bilirubin in protection against oxidative stress remains to be established. In the present study, we examined the dynamics of HO-1 expression and bilirubin production after stimulation of vascular smooth-muscle cells with hemin, a potent inducer of the HO-1 gene. We found that hemin-mediated increase in HO-1 protein expression and haem oxygenase activity is associated with augmented bilirubin levels. The majority of bilirubin production occurred early after exposure of cells to hemin. Hemin pre-treatment also resulted in high resistance to cell injury caused by an oxidant-generating system. Interestingly, this protective effect was manifest only when cells were actively producing bilirubin as a consequence of increased haem availability and utilization by HO-1. Tin protoporphyrin IX, an inhibitor of haem oxygenase activity, significantly reduced bilirubin generation and reversed cellular protection afforded by hemin treatment. Furthermore, addition of bilirubin to the culture medium markedly reduced the cytotoxicity produced by oxidants. Our findings provide direct evidence that bilirubin generated after up-regulation of the HO-1 pathway is cytoprotective against oxidative stress.

Animals↗
PubMed2005

[Effects of Losartan on expression of heme oxygenases in volume-overloaded rats with left-to-right shunt].

OBJECTIVE: To study the expression of heme oxygenase-1 mRNA and pulmonary remodeling before and after surgical establishment of left-to-right shunt in volume-overloaded SD rats and rats with Losartan intervention. METHODS: Left-to-right shunt volume-overloaded SD rat models were established by aortocaval shunt operation. Seven rats with shunt were placed on Losartan (Losartan group), 7 rats with but not given Losartan were included in the operation group, and 4 rats after sham operation served as controls. Pulmonary pressure and right ventricular pressure were measured during catheterization. The relative weights ventricles were determined after execution of the rats. Pulmonary vascular remodeling parameters, including percentage arterial wall thickness and percentage muscularized small arteries, were assessed by morphometry. Heme oxygenase-1 (HO-1) mRNA expression and heme oxygenase-2 (HO-2) mRNA expression were detected RT-PCR method. RESULTS: Pulmonary artery pressure and right ventricular relative weight decreased significantly in the rats of Losartan group; in addition, the percentage arterial wall thickness and percentage of muscularized small arteries in the Losartan group were reduced as compared with those in the operation group. The level 1 mRAN expression in rats with shunt was significantly higher than that in rats without shunt. The level mRNA expression in the Losartan group decreased remarkably as compared against that in the operation The level of HO-1 mRNA expression in lungs was significantly higher than that in ventricles. There statistically significant differences in HO-2 mRNA expression levels between the three rat groups. CONCLUSION: Losartan intervention can markedly reduce pulmonary pressure, inhibit vascular remodeling in volume-overloaded left-to-right shunt rats, and result in down-regulation of HO-1 mRNA expression.

Animals↗
PubMed1989

Targeting of heme oxygenase inhibitors to the spleen markedly increases their ability to diminish bilirubin production.

Incorporation of heme oxygenase inhibitors into phosphatidyl choline liposomes markedly enhanced localization of these agents within the spleen as compared with the localization observed following their administration in aqueous vehicle. The increased concentration of inhibitor within splenic microsomes led to a near complete and sustained blockade of heme oxygenase activity and thus to a marked diminution in biliary bilirubin output. These studies suggest that heme oxygenase inhibitors administered within liposomes may so effectively block bilirubin production in the human newborn that ancillary methods for treating this important clinical problem may be reduced to a minimum.

Animals↗
PubMed1989

Transcriptional control of the rat heme oxygenase gene by a nuclear protein that interacts with adenovirus 2 major late promoter.

Induction of rat heme oxygenase is mediated by at least two factors: its substrate heme and heat shock (Shibahara, S., Müller, R.M., and Taguchi, H. (1987) J. Biol. Chem. 262, 12889-12892). We have identified the cis-acting element of the rat heme oxygenase gene (HO gene), that was specifically bound by a nuclear protein prepared from rat glioma cells. We have termed this protein as heme oxygenase transcription factor (HOTF), whose estimated molecular weight is about 40,000. The element identified is CCACCACGTGACTCGAG (-51/-35) located just upstream of TATA-like sequence. The functional studies indicate that this sequence is required for the accurate and efficient initiation of transcription from the HO gene promoter. Since the HOTF-binding element is similar to the upstream promoter sequence (UPS) of the adenovirus 2 major late promoter (Ad2MLP), we examined whether rat HOTF is homologous to the upstream stimulatory factor (USF) or major late transcription factor previously identified in HeLa cells, which interacts with the UPS and activates the transcription from the Ad2MLP. HOTF specifically binds to the UPS of Ad2MLP, whereas HOTF failed to form a stable complex with the mutated HOTF-binding element lacking a GTGA sequence (-44/-42 of the HO gene), the sequence of which is identical to a core sequence of the USF-binding sites. Moreover, we show that like USF, HOTF is heat stable. These results suggest that HOTF may be homologous to USF or the major late transcription factor. Since USF is present in uninfected cells, it is conceivable that the expression of the HO gene is regulated at least in part by USF.

Adenoviruses, Human↗