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

Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.
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PMID:Ferritin: a cytoprotective antioxidant strategem of endothelium. 151 45

1. The distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry in the pig's lower urinary tract, including bladder extramural arteries, and the oesophagogastric junction (OGJ). In isolated smooth muscle from the urethra and the OGJ, the mechanisms for CO-induced relaxations were characterized by measurement of cyclic nucleotide levels and by responses to the guanylate cyclase inhibitor methylene blue and some K+ channel inhibitors. 2. HO-2 immunoreactivity was observed in coarse nerve trunks within the smooth muscle of the urethra and OGJ, and in nerve cell bodies of the enteric plexuses of the OGJ. Furthermore, the vascular endothelium of the intramural vessels of the urethra, bladder and OGJ, and the extramural vessels of the bladder, displayed HO-2 immunoreactivity. Two different antisera against HO-1 were used, but only one displayed immunoreactivity in neuronal structures. HO-1 immunoreactivity, as displayed by this antiserum, was seen in nerve cells, coarse nerve trunks and varicose nerve fibres in the smooth muscle of the urethra and OGJ. Some HO-2 and/or HO-1 (as displayed by both HO-1 antisera) immunoreactive cells with a non-neuronal appearance were observed within the smooth muscle of the OGJ, bladder and urethra. 3. In the urethral preparations, exogenously applied CO (72 microM) evoked a relaxation amounting to 76 +/- 6%. The relaxation was associated with an increase in cyclic GMP, but not cyclic AMP, content. CO-evoked relaxations were not significantly reduced by treatment with methylene blue, or by inhibitors of voltage-dependent (4-aminopyridine), high (iberiotoxin, charybdotoxin) and low (apamin) conductance Ca(2+)-activated, and ATP-sensitive (glibenclamide) K+ channels. Bladder strips, and ring preparations from the extramural arteries of the bladder, did not respond to exogenously administered CO (12-72 microM). 4. In the OGJ, exogenously applied CO evoked a relaxation of 86 +/- 6%, which was associated with an increase in cyclic GMP, but not cyclic AMP, content. Treatment with 30 microM methylene blue raised the spontaneously developed muscle tone, and reduced the maximum relaxation evoked by CO to 33 +/- 9%. Addition of 4-aminopyridine, apamin, glibenclamide, iberiotoxin, charybdotoxin or glibenclamide had no effect on the relaxations. 4-aminopyridine (0.1-1 mM), iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM) increased the spontaneously developed tone, and a combination of charybdotoxin and apamin reduced CO-induced (24 microM CO) relaxations. 5. The present findings demonstrate the presence of HO in both neuronal and non-neuronal cells in the pig OGJ and lower urinary tract. CO produces relaxation of the smooth muscle in the OGJ and urethra, associated with a small increase in cyclic GMP concentration in both regions. Relaxations evoked by CO in the urethra do not seem to involve voltage-dependent, low and high conductance, or ATP-dependent K+ channels. However, in the OGJ relaxations evoked by CO can be attenuated by methylene blue and a combination of charybdotoxin and apamin.
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PMID:Carbon monoxide-induced relaxation and distribution of haem oxygenase isoenzymes in the pig urethra and lower oesophagogastric junction. 911 25

Carbon monoxide (CO), produced by haem oxygenase (HO), has been suggested as a messenger molecule in the central and peripheral nervous systems. In the present study, we have investigated the occurrence of the two isoforms of HO, HO-2 and HO-1 in the canine and feline gastrointestinal tracts, including the small and large intestine and the gastrointestinal sphincters. An abundance of nerve cell bodies that contained immunoreactivity for HO-2 was found in the submucosal and myenteric plexuses. HO-2 immunoreactivity was frequently co-localized with nitric oxide synthase (NOS) or vasoactive intestinal peptide (VIP) immunoreactivities and was also observed in some nerve fibres, certain non-neuronal cells dispersed among smooth muscle bundles, and in vascular endothelium. The antiserum against HO-1 revealed immunoreactivity in nerve cell bodies in the enteric plexuses, in nerve fibres and in non neuronal cells in the smooth muscle layers. Some of the nerve structures were also NOS- or VIP-immunoreactive. These results demonstrate the presence of HO isoenzymes in nerves and other structures of the canine and feline gastrointestinal tracts and support the view that CO may have a role as a messenger molecule in the enteric nervous system.
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PMID:Morphological relations between haem oxygenases, NO-synthase and VIP in the canine and feline gastrointestinal tracts. 925 72

Portal hypertension is associated with a wide range of pulmonary pathophysiologies, ranging from portopulmonary hypertension to hepatopulmonary syndrome. Although the clinical and pathological features of pulmonary dysfunction in this setting have been extensively characterized, the underlying biology is not well understood. Specifically, the role of mediators that regulate mesenteric vascular hemodynamics in portal hypertension, such as nitric oxide and endothelin, have not been studied in the lung. Using a rat model of prehepatic portal hypertension with preserved hepatic function, we examined pulmonary elaboration of endothelial nitric oxide synthase (NOS), inducible NOS, heme oxygenase- 1 (HO-1), heme oxygenase-2 (HO-2), endothelin-1 mRNA, and protein. In comparison to sham controls, portal hypertensive animals exhibited significantly increased pulmonary iNOS and HO-1 mRNA and protein. Cyclic GMP was significantly increased in portal hypertensive lung tissue, suggesting activation of guanylyl cyclase by the endproducts of iNOS and/or HO-1 activity. Using immunohistochemical analysis, iNOS expression was localized to the vascular endothelium, while HO-1 localized to bronchiolar epithelium and macrophages. These results suggest that production of nitric oxide and carbon monoxide may contribute to the pulmonary pathology associated with portal hypertension.
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PMID:Pulmonary expression of iNOS and HO-1 protein is upregulated in a rat model of prehepatic portal hypertension. 1125 66

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.
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PMID:Estrogen increases endothelial carbon monoxide, heme oxygenase 2, and carbon monoxide-derived cGMP by a receptor-mediated system. 1150 20

Carbon monoxide (CO) is produced by the action of the heme oxygenase (HO) complex through the oxidation of heme. CO, like nitric oxide (NO), is a molecular gas that among other actions stimulates guanylyl cyclase and increases cGMP levels in smooth muscle cells, regulating the vascular tone. Acute hypoxia generates pulmonary hypertension and increases the expression of inducible HO isoform (HO-1) in the vascular endothelium. Inhaled NO causes a potent pulmonary vasodilation. We hypothesized that inhaled CO might produce similar actions as NO on pulmonary vascular resistance (PVR). To test our contention, we studied the effects of inhaled CO (40 ppm) in the augmented PVR observed during hypoxemia. Five chronically instrumented German Merino sheep were submitted to a protocol consisting of 20 min of normoxemia (N), 20 min of isocapnic hypoxemia (H20), 20 min of isocapnic hypoxemia plus CO 40 ppm (H40), and 20 min of recovery (R). In the control protocol, we did not administer inhaled CO. Arterial gases and pH, percentage of carboxyhemoglobin (COHb), systemic and pulmonary arterial pressure, systemic and pulmonary vascular resistance, and cardiac output were measured during each period. During H20 period, there was a significant increase in cardiac output and PVR in sheep submitted to both protocols. The sheep treated with inhaled CO (H40 + CO) showed a modest but significant decrease (16%) in the elevated PVR. Our data indicate that inhaled CO decreases pulmonary vascular resistance associated with acute hypoxemia in adult sheep.
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PMID:Low-dose inhaled carbon monoxide reduces pulmonary vascular resistance during acute hypoxemia in adult sheep. 1168 17

Vasodilator effects of glutamate in the cerebral circulation are, in part, mediated by carbon monoxide (CO), which is formed from heme via the heme oxygenase (HO) pathway. The hypothesis addressed was that glutamate receptors (GluRs) in cerebral microvascular endothelium are functionally linked to HO. Using a radioligand binding and immunoblotting, GluRs were characterized in cerebral microvascular endothelial cells (CMVEC) from newborn pigs. High-affinity (80 nmol/L) reversible binding of [3H]glutamate ([ 3H]Glu) was detected in CMVEC membranes. The -methyl-d-aspartate (NMDA) receptor ligands-NMDA, quinolinic acid, (+/-)1-aminocyclopentane- -1,3-dicarboxylic acid ( ACPD), AP5, 4C3HPG, and CPP-and the (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor ligands-AMPA, kainic acid, quisqualic acid, DNQX, and CNQX-displaced 20% to 30% of bound [3H]Glu in CMVEC membranes. Metabotropic GluRs antagonists (4CPG, PHCC, and CPPG) did not displace bound [3H]Glu. l-Aspartate, an agonist of GluRs and glutamate transporters, displaced 80% or more of bound [3H]Glu. Ionotropic (NR1 and GluR1) and metabotropic (mGluR1alpha) GluRs were detected in CMVEC by immunoblotting. Glutamate, aspartate, ACPD, AMPA, (RS)-2-amino-(3-hydroxy-5- -butylisoxazol-4-yl)propanoic acid (ATPA), and kainate (10(-5) mol/L) increased HO-directed CO formation by isolated cerebral microvessels and by cultured CMVEC. These data in newborn pigs suggest that CMVEC express ionotropic GluRs that are functionally linked to HO. GluR-mediated increases in CO formation by vascular endothelium may result in increase in cerebral blood flow.
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PMID:Ionotropic glutamate receptors in cerebral microvascular endothelium are functionally linked to heme oxygenase. 1257 50

Heme oxygenase (HO) has been primarily regarded as the rate-limiting enzyme in the degradation of heme. However it has recently been proposed that the inducible isoform, HO-1 (EC 1.14.99.3), functions as a stress-responsive antioxidant enzyme, with the capacity to protect against oxidant-mediated vascular injury. This study used an in vitro model of endothelial permeability to determine the effects of the HO-1-inducing agent hemin on noncytotoxic endothelial injury mediated by acute oxidant stress. Effects of hemin on oxidant-mediated cytotoxicity in a number of endothelial cell types were also investigated. A 20-min exposure of human umbilical vein endothelial cell (HUVEC) monolayers to H(2)O(2) resulted in a significant concentration-dependent increase in permeability, which was reversible 48 h later. Pretreatment of monolayers with hemin for 2 h followed by 18 h in complete medium resulted in HO-1 induction and the attenuation of H(2)O(2)-mediated increases in endothelial permeability, and significantly improved the restoration of endothelial barrier function 48 h later. In HUVEC and in the human microvascular endothelial cell line HMEC-1, hemin treatment as above resulted in protection against cytotoxicity, but not in bovine aortic endothelial cells (BAECs), where such toxicity was potentiated. This potentiation was inhibited by incubation with the HO inhibitor tin protoporphyrin IX, supporting a role for HO-1 in the potentiation of the cytotoxic response. When the exposure time of BAEC to hemin was extended to 24 h, H(2)O(2)-mediated cytotoxicity was attenuated. We conclude that hemin treatment is cytoprotective against noncytotoxic endothelial injury in vitro, under conditions that may not offer global protection against cytotoxic injury to vascular endothelium. This would indicate that HO-1 induction associated with cytotoxic injury in vivo is not always beneficial and therefore that the use of hemin as a therapeutic agent to offset oxidant injury in vascular endothelium should be undertaken with caution.
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PMID:Role of hemin in the modulation of H2O2-mediated endothelial cell injury. 1264 99

Iron-derived reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic haemolytic anaemia, vasculitis and reperfusion injury. One abundant source of redox-active iron is haem, which is inherently dangerous when released from intracellular haem proteins. The present review concerns the likely involvement of haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free haem also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer haem to endothelium, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defence against such toxicity, upon exposure to free haem, endothelial cells up-regulate haem oxygenase-1 and ferritin. Haem oxygenase is a haem-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide and a most dangerous product-free redox-active iron. The latter can be controlled effectively by sequestration within ferritin, a multimeric protein with a very high capacity for storing iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous haem and oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.
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PMID:Haem, haem oxygenase and ferritin in vascular endothelial cell injury. 1281 58

Carbon monoxide (CO) is an endogenously produced gas mediator produced by heme oxygenase (HO). Like nitric oxide (NO), CO is produced in the nasal mucosa. Given that induced NO synthase (iNOS) expression in nasal mucosa has been found to be up-regulated in allergic rhinitis, the current study investigated the expression of HO isoforms in allergic human nasal mucosa. Immunohistochemical staining for type 1 and 2 HO isoforms were carried out in nasal inferior turbinate mucosa from six patients with persistent allergic rhinitis, and compared with six control patients without nasal allergy. Focal and weak expression of HO-1 was observed in seromucous glands, with no difference between allergic and control specimens. Vascular endothelium, erythrocytes, smooth muscle and inflammatory cells (except macrophages) in the allergic group exhibited stronger HO-1 immunoreactivity compared to the control. Minimal expression was found in the respiratory epithelium in either group. Intravascular HO-1 expression was found in the allergic mucosa only. Intense HO-2 immunoreactivity was observed in the respiratory epithelium, vascular endothelium and seromucous glands in both allergic and control groups with no differences in intensity. In conclusion, unlike iNOS, HO-1 is minimally expressed in the nasal respiratory epithelium of either group. However, our findings suggest that it may be involved in the inflammatory process of allergic rhinitis at the submucosal level.
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PMID:Localisation of heme oxygenase isoforms in allergic human nasal mucosa. 1559 35


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