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)

Carbon monoxide has been shown to act as a neurotransmitter and neuronal messenger in the brain. Heme oxygenase catalyzes the conversion of heme to carbon monoxide and biliverdin. We have recently reported that carbon monoxide was involved in central cardiovascular regulation. Carbon monoxide modulated the baroreflex and may affect glutamatergic neurotransmission. In addition, metabotropic glutamate receptors may be coupled to the activation of heme oxygenase in the nucleus tractus solitarii of rats. The present study was designed to investigate the possible interactions of carbon monoxide and metabotropic glutamate receptor groups in the nucleus tractus solitarii. Unilateral microinjection of several agonists for metabotropic glutamate receptor groups such as (R,S)-3,5-dihydroxyphenylglycine (DHPG) (group I) (0.03 nmol), 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) (group II) (0.3 nmol), and l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) (group III) (0.3 nmol) produced a significant decrease in blood pressure and heart rate. Among the metabotropic glutamate receptor agonists, prior administration of zinc protoporphyrin IX, an inhibitor of heme oxygenase activity, significantly attenuated the cardiovascular effects of APDC and l-AP4, and failed to attenuate the cardiovascular responses of DHPG. These results indicated interactions between carbon monoxide and group II and III metabotropic glutamate receptors in central cardiovascular regulation.
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PMID:Interactions of carbon monoxide and metabotropic glutamate receptor groups in the nucleus tractus solitarii of rats. 1461 88

The hypothesis was addressed that CO-induced cerebral vasodilation requires a permissive cGMP signal that can be produced by nitric oxide (NO). Anesthetized piglets were implanted with cranial windows for measurement of pial arteriolar responses to stimuli. Pial arterioles dilated in response to isoproterenol (Iso), sodium nitroprusside (SNP), and CO or the CO-releasing molecule Mn2(CO)10 [dimanganese decacarbonyl (DMDC)]. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, decreased cerebrospinal fluid (CSF) cGMP and selectively inhibited dilations to SNP and DMDC without affecting the dilation to Iso. However, DMDC did not cause an increase in cortical periarachnoid CSF cGMP concentration. cGMP clamp with a threshold dilator level of 8-bromo-cGMP (10(-4) M) and ODQ restored the dilation to DMDC that had been blocked by ODQ alone. Under these conditions, cGMP was present but could not increase. Inhibition of the pial arteriolar dilation to glutamate by N-nitro-l-arginine, which blocks NO synthase, was similar to that by heme oxygenase inhibitors, which block endogenous CO production. The dilation to glutamate, similar to dilation to DMDC, was partially restored by 8-bromo-cGMP and completely restored by SNP (5 x 10(-7) M). These data suggest that the permissive role of NO in CO- and glutamate-induced vasodilation involves maintaining the minimum necessary cellular level of cGMP to allow CO to cause dilation independently of increasing cGMP.
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PMID:Role of cGMP in carbon monoxide-induced cerebral vasodilation in piglets. 1468 63

The activity of hepatic heme oxygenase (HO) in rats is elevated in response to copper deficiency. However, the mechanism responsible for the increase in HO activity is poorly understood. Oxidative stress is a common denominator for many of the signals that induce HO-1, the inducible isoform of HO. The present study evaluated the role of H(2)O(2) and the mitochondrial electron transport chain as a potential mechanism for the induction of HO-1 during copper deficiency. Mitochondria isolated from the livers of young male rats fed a copper-deficient diet for 5 wk had significantly (P < 0.05) reduced levels of NADH:cytochrome c reductase (31% reduction), succinate:cytrochrome c reductase (42% reduction), and cytochrome c oxidase (70% reduction) activities and significantly increased production of H(2)O(2) (48% increase) when glutamate was used as a substrate. Hepatic levels of HO-1 protein and mRNA were also significantly elevated (48 and 20%, respectively) in copper-deficient rats, indicating that copper deficiency stimulated the expression of the HO-1 gene. Furthermore, hepatic HO-1 protein content was best described by a regression model that included mitochondrial NADH:cytochrome c reductase and succinate:cytochrome c reductase activities, but not cytochrome c oxidase activity (R(2) = 0.54, P < 0.02). Hydrogen peroxide is a known inducer of HO-1, and our results suggest that increased mitochondrial H(2)O(2) production resulting from inhibition of respiratory complex activities contributes to the induction of HO-1 during copper deficiency. The levels of HO-1 protein and mRNA were also elevated (85 and 95%, respectively) in hearts from copper-deficient rats, indicating that the effects of copper deficiency on HO-1 gene expression are not limited to hepatic tissue.
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PMID:Increased heme oxygenase-1 expression during copper deficiency in rats results from increased mitochondrial generation of hydrogen peroxide. 1517 92

The heme oxygenase family of enzymes catalyzes the metabolism of heme to biliverdin, ferrous iron, and carbon monoxide (CO). At least two isoforms exist, heme oxygenase-1 (HO1) and heme oxygenase-2 (HO2), which are encoded by separate genes. HO2 is selectively enriched in neurons, and substantial evidence suggests that HO2-derived CO functions as a neurotransmitter/neuromodulator. However, a molecular mechanism for the rapid activation of HO2 during neuronal activity has not been described. Through a yeast two-hybrid screen we identified calmodulin as a potential regulator of HO2 activity. Calmodulin binds with nanomolar affinity to HO2 in a calcium-dependent manner via a canonical 1-10 motif, resulting in a 3-fold increase in catalytic activity. Mutations within this motif block calmodulin binding and calcium-dependent stimulation of enzyme activity in vitro and in intact cells. The calcium mobilizing agents ionomycin and glutamate stimulate endogenous HO2 activity in primary cortical cultures, establishing in vivo relevance. Calcium-calmodulin provides a mechanism for rapid and transient activation of HO2 during neuronal activity.
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PMID:Heme oxygenase-2 is activated by calcium-calmodulin. 1517 37

Induction of CYP2E1 by ethanol is one pathway through which ethanol generates oxidative stress. Nrf2 is a transcription factor that regulates important antioxidant and phase II detoxification genes. Nrf2 induction by CYP2E1 and its importance in the adaptive response to increased oxidative stress caused by CYP2E1 was studied. Increases in Nrf2 protein and mRNA were observed in livers or hepatocytes of chronic alcohol-fed mice or rats and of pyrazole-treated rats or mice, conditions known to elevate CYP2E1. HepG2 cells expressing CYP2E1 (E47 cells) showed increased Nrf2 mRNA and protein expression compared with control HepG2 C34 cells. Nrf2 is activated in E47 cells as shown by an increase in nuclear Nrf2 levels and Nrf2-antioxidant-responsive element binding activity, and upregulation of Nrf2-regultated genes, glutamate cysteine ligase catalytic subunit (GCLC), and heme oxygenase 1 (HO-1). Increases in Nrf2 protein and mRNA are blocked by inhibitors of CYP2E1 activity and a reactive oxygen species (ROS) scavenger, N-acetylcysteine, which decrease ROS levels as well as Nrf2 mRNA induction. Upregulation of GCLC and HO-1 in E47 cells is dependent on Nrf2 and is prevented by siRNA-Nrf2. Blocking Nrf2 by siRNA-Nrf2 decreases glutathione and increases ROS and lipid peroxidation, resulting in decreased mitochondrial membrane potential and loss of cell viability of E47 cells but not C34 cells. These results suggest that Nrf2 is activated and that levels of protein and mRNA are increased when CYP2E1 is elevated. In conclusion, Nrf2 plays a key role in the adaptive response against increased oxidative stress caused by CYP2E1.
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PMID:Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1. 1637 48

Up-regulation of heme oxygenase (HO-1) by either cobalt protoporphyrin (CoPP) or human gene transfer improves vascular and renal function by several mechanisms, including increases in antioxidant levels and decreases in reactive oxygen species (ROS) in vascular and renal tissue. The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase, and anti-apoptotic proteins in diabetic rats (streptozotocin, (STZ)-induced type 1 diabetes). Renal mitochondrial carnitine, deoxynucleotide, and ADP/ATP carriers were significantly reduced in diabetic compared with nondiabetic rats (p < 0.05). The citrate carrier was not significantly decreased in diabetic tissue. CoPP administration produced a robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate, and ADP/ATP carriers and no significant change in oxoglutarate and aspartate/glutamate carriers. The increase in mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity. The administration of tin mesoporphyrin (SnMP), an inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats. Human HO-1 cDNA transfer into diabetic rats increased both HO-1 protein and activity, and restored mitochondrial ADP/ATP and deoxynucleotide carriers. The increase in HO-1 by CoPP administration was associated with a significant increase in the phosphorylation of AKT and levels of BcL-XL proteins. These observations in experimental diabetes suggest that the cytoprotective mechanism of HO-1 against oxidative stress involves an increase in the levels of MCs and anti-apoptotic proteins as well as in cytochrome c oxidase activity.
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PMID:Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes. 1659 61

Heme oxygenase is a rate-limiting enzyme that degrades heme, a pro-oxidant, into carbon monoxide, iron, and bilirubin. Heme oxygenase has two active isoforms: heme oxygenase-1 and heme oxygenase-2. Heme oxygenase-1 can be induced by various insults. Several investigators have postulated that it has cytoprotective activities, although its role in the nervous system is not fully understood, especially considering that normally heme oxygenase-2 accounts for the vast majority of heme oxygenase activity in the brain. Here, the basal effect of heme oxygenase-1 was investigated in acute glutamatergic excitotoxicity to test the hypothesis that N-methyl-D-aspartate-induced acute toxicity in brain is attenuated by heme oxygenase-1. N-methyl-D-aspartate was unilaterally injected into the striatum of wildtype and heme oxygenase-1 knockout mice. After 48 h, brains were harvested, sectioned, and stained with Cresyl Violet to measure the lesion size. Lesion volume was significantly (P<0.05) greater in brains of heme oxygenase-1 knockout mice (15.2+/-3.1 mm(3); n=10) than in those of wildtype mice (6.2+/-1.5 mm(3); n=11). In addition, Western blot analysis indicated no detectable differences between wildtype and heme oxygenase-1 knockout mouse brains in the levels of the glutamate or N-methyl-D-aspartate receptors studied. To test whether heme oxygenase-1 could specifically protect neurons, mouse primary neuronal cell cultures of wildtype and heme oxygenase-1 knockout mice were treated with or without N-methyl-D-aspartate. Cell viability of the heme oxygenase-1 knockout neurons was significantly less than that of wildtype neurons at each of the N-methyl-D-aspartate concentrations tested (12.8+/-1.3%, 16.0+/-1.4%, and 18.4+/-1.8% at 30, 100, and 300 microM N-methyl-D-aspartate, respectively). These results indicate that heme oxygenase-1 provides neuroprotection against acute excitotoxicity and suggest that potential intervention that can increase heme oxygenase-1 activity within the brain should be considered as a therapeutic target in acute and potentially chronic neurological disorders.
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PMID:Heme oxygenase-1 protects brain from acute excitotoxicity. 1682 75

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) contains two transcription activation domains, Neh4 (Nrf2 ECH homology 4) and Neh5, which co-ordinately regulate transactivation of cytoprotective genes. In the present study we aimed to clarify the role of the Neh5 domain in Nrf2-mediated gene regulation. Deletion of the complete Neh5 domain reduces expression of endogenous Nrf2 target genes, such as HO-1 (haem oxygenase 1), NQO1 [NAD(P)H:quinone oxidoreductase 1] and GCLM (glutamate cysteine ligase modulatory subunit), in human kidney epithelial cells. Furthermore, the deletion of Neh5 markedly repressed CBP [CREB (cAMP-response-element-binding protein)-binding protein] and BRG1 (Brahma-related gene 1) from associating with Nrf2, diminishing their co-operative enhancement of HO-1 promoter activity. Mutational analysis of the Neh5 domain revealed a motif that shares significant homology with beta-actin and ARP1 (actin-related protein 1). Mutagenesis of this motif selectively decreased HO-1, but not NQO1 and GCLM, expression. Taken together, these results indicate that the Neh5 domain has the ability to regulate Nrf2 target gene transcription, yet the role of the Neh5 domain in transcription varies from gene to gene.
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PMID:Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes. 1731 70

Large-conductance calcium-activated potassium (K(Ca)) channels regulate the physiological functions of many tissues, including cerebrovascular smooth muscle. l-Glutamic acid (glutamate) is the principal excitatory neurotransmitter in the central nervous system, and oxygen tension is a dominant local regulator of vascular tone. In vivo, glutamate and hypoxia dilate newborn pig cerebral arterioles, and both dilations are blocked by inhibition of carbon monoxide (CO) production. CO dilates cerebral arterioles by activating K(Ca) channels. Therefore, the present study was designed to investigate the effects of glutamate and hypoxia on cerebral CO production and the role of K(Ca) channels in the cerebral arteriolar dilations to glutamate and hypoxia. In the presence of iberiotoxin or paxilline that block dilation to the K(Ca) channel opener, NS-1619, neither CO nor glutamate dilated pial arterioles. Conversely, neither paxilline nor iberiotoxin inhibited dilation to acute severe or moderate prolonged hypoxia. Both glutamate and hypoxia increased cerebrospinal fluid (CSF) CO concentration. Iberiotoxin that blocked dilation to glutamate did not attenuate the increase in CSF CO. The guanylyl cyclase inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), which blocked dilation to sodium nitroprusside, did not inhibit dilation to hypoxia. These data suggest that dilation of newborn pig pial arterioles to glutamate is mediated by activation of K(Ca) channels, consistent with the intermediary signal being CO. Surprisingly, although 1) heme oxygenase (HO) inhibition attenuates dilation to hypoxia, 2) hypoxia increases CSF CO concentration, and 3) K(Ca) channel antagonists block dilation to CO, neither K(Ca) channel blockers nor ODQ altered dilation to hypoxia, suggesting the contribution of the HO/CO system to hypoxia-induced dilation is not by stimulating vascular smooth muscle K(Ca) channels or guanylyl cyclase.
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PMID:Carbon monoxide and Ca2+-activated K+ channels in cerebral arteriolar responses to glutamate and hypoxia in newborn pigs. 1776 83

Astrocyte signals can modulate arteriolar tone, contributing to regulation of cerebral blood flow, but specific intercellular communication mechanisms are unclear. Here we used isolated cerebral arteriole myocytes, astrocytes, and brain slices to investigate whether carbon monoxide (CO) generated by the enzyme heme oxygenase (HO) acts as an astrocyte-to-myocyte gasotransmitter in the brain. Glutamate stimulated CO production by astrocytes with intact HO-2, but not those genetically deficient in HO-2. Glutamate activated transient K(Ca) currents and single K(Ca) channels in myocytes that were in contact with astrocytes, but did not affect K(Ca) channel activity in myocytes that were alone. Pretreatment of astrocytes with chromium mesoporphyrin (CrMP), a HO inhibitor, or genetic ablation of HO-2 prevented glutamate-induced activation of myocyte transient K(Ca) currents and K(Ca) channels. Glutamate decreased arteriole myocyte intracellular Ca2+ concentration and dilated brain slice arterioles and this decrease and dilation were blocked by CrMP. Brain slice arteriole dilation to glutamate was also blocked by L-2-alpha aminoadipic acid, a selective astrocyte toxin, and paxilline, a K(Ca) channel blocker. These data indicate that an astrocytic signal, notably HO-2-derived CO, is used by glutamate to stimulate arteriole myocyte K(Ca) channels and dilate cerebral arterioles. Our study explains the astrocyte and HO dependence of glutamatergic functional hyperemia observed in the newborn cerebrovascular circulation in vivo.
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PMID:Astrocyte-derived CO is a diffusible messenger that mediates glutamate-induced cerebral arteriolar dilation by activating smooth muscle Cell KCa channels. 1799 80


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