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

We investigated the role of carbon monoxide as a neural modulator of extracellular glutamate concentration in rat hippocampus CA1 in transient forebrain ischemia by using metalloporphyrins, which block the production of carbon monoxide through the inhibition of heme oxygenase (HO) activity. Infusion of 10 and 100 microM zinc protoporphyrin IX, which inhibits nitric oxide synthase activity as well as HO activity, significantly increased glutamate concentration compared with that on the vehicle-treated side. However, infusion of 100 microM tin mesoporphyrin IX, which inhibits only HO activity, did not affect glutamate concentration in ischemia. Our results therefore do not support the hypothesis that carbon monoxide acts as a neural messenger through the modulation of extracellular glutamate concentration in ischemia.
J Cereb Blood Flow Metab 1996 Sep
PMID:Carbon monoxide, a novel neural messenger, does not modulate extracellular glutamate concentration in forebrain ischemia. 878 53

Recent studies strongly suggest that oxidative stresses participate in ischemia/reperfusion-induced neurodegeneration. In addition, heme oxygenase (HO) and major histocompatibility complex (MHC) antigens serve as functional molecules against oxidative stress and as self-recognition markers in the immune system, respectively. In this study, we examined the induction of HO and MHC antigens in the rat hippocampus after transient forebrain ischemia. The protein level of HO-1 was significantly enhanced after an episode of ischemia. After ischemia, HO-1 expression was observed early but transiently in the CA1 pyramidal neurons and later but continuously in glial cells. Glial cells expressing HO-1 were predominantly ameboid microglia, but not astrocytes. Ameboid microglia expressing HO-1 were predominantly localized with MHC class II antigens. These results indicate that (1) HO-1 expression in CA1 pyramidal neurons may be harmful, and (2) ischemia induces HO-1 in ameboid microglia that express MHC class II antigens, indicating a very specific microglial stress protein response.
J Cereb Blood Flow Metab 1998 Aug
PMID:Induction of heme oxygenase-1 and major histocompatibility complex antigens in transient forebrain ischemia. 970 43

Hemoglobin is a key factor in the production of cerebral vasospasm. Metabolism of hemoglobin involves breakdown of heme by heme oxygenase (HO) and sequestration of the released iron in ferritin. We determined whether subarachnoid hemorrhage induces these proteins in cerebral arteries and, if so, in which cells they are produced. Whether the changes correlated with vasospasm also was investigated. Subarachnoid hemorrhage was created in monkeys, and vasospasm was assessed by angiography in cohorts of animals killed 3, 7, or 14 days after the hemorrhage. Ferritin and HO-1 messenger ribonucleic acid (mRNA) and protein were measured by competitive reverse transcription-polymerase chain reaction and Western blotting in hemorrhage-side and control-side cerebral arteries and brain tissue. The location of these proteins was determined by immunohistochemistry. There was significant vasospasm 3 and 7 days but not 14 days after subarachnoid hemorrhage. There were no significant changes in mRNA for HO-1 or ferritin in cerebral arteries or brain tissue at any time. There was a significant increase in HO-1 and ferritin protein in hemorrhage-side compared with control-side cerebral arteries at 3, 7, and 14 days. The increase in HO-1 protein was maximal at 3 days, whereas the increase in ferritin protein was maximal at 7 days. There was no detectable increase in HO-1 or ferritin protein in brain tissue at any time. Immunohistochemistry localized HO-1 protein and ferritin to cells in the adventitia of the arterial wall. We show that subarachnoid hemorrhage is associated with a significant increase in HO-1 and ferritin proteins in cerebral arteries that begins at least as early as 3 days after the hemorrhage and that persists for up to 14 days.
J Cereb Blood Flow Metab 2000 Jul
PMID:Heme oxygenase-1 and ferritin are increased in cerebral arteries after subarachnoid hemorrhage in monkeys. 1090 40

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.
J Cereb Blood Flow Metab 2003 Feb
PMID:Ionotropic glutamate receptors in cerebral microvascular endothelium are functionally linked to heme oxygenase. 1257 50

Heme and iron metabolism are of considerable interest and importance in normal brain function as well as in neurodegeneration and neuropathologically following traumatic injury and hemorrhagic stroke. After a cerebral hemorrhage, large numbers of hemoglobin-containing red blood cells are released into the brain's parenchyma and/or subarachnoid space. After hemolysis and the subsequent release of heme from hemoglobin, several pathways are employed to transport and metabolize this heme and its iron moiety to protect the brain from potential oxidative stress. Required for these processes are various extracellular and intracellular transporters and storage proteins, the heme oxygenase isozymes and metabolic proteins with differing localizations in the various brain-cell types. In the past several years, additional new genes and proteins have been discovered that are involved in the transport and metabolism of heme and iron in brain and other tissues. These discoveries may provide new insights into neurodegenerative diseases like Alzheimer's, Parkinson's, and Friedrich's ataxia that are associated with accumulation of iron in specific brain regions or in specific organelles. The present review will examine the uptake and metabolism of heme and iron in the brain and will relate these processes to blood removal and to the potential mechanisms underlying brain injury following cerebral hemorrhage.
J Cereb Blood Flow Metab 2003 Jun
PMID:Heme and iron metabolism: role in cerebral hemorrhage. 1279 11

The cerebrovascular effects of the heme oxygenase-carbon monoxide pathway were studied in the rat hypothalamus. Intraperitoneal administration of the heme oxygenase inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG, 45 micro mol/kg) had no significant effect on the resting cerebral blood flow, but increased hypothalamic nitric oxide synthase activity by 67% without changing the CSF cyclic GMP concentration. After pharmacologic inhibition of nitric oxide synthase, the diminished cerebral blood flow was further reduced by 22% after administration of ZnDPBG, and the effect showed direct correlation with the baseline perfusion level. Therefore, endogenous carbon monoxide may significantly contribute to the cerebral vasoregulation under resting conditions and in pathophysiologic states associated with diminished nitric oxide synthesis.
J Cereb Blood Flow Metab 2003 Jun
PMID:Contribution of the heme oxygenase pathway to the maintenance of the hypothalamic blood flow during diminished nitric oxide synthesis. 1279 12

Delayed cerebral vasospasm after subarachnoid hemorrhage (SAH) remains a significant cause of mortality and morbidity; however, the etiology is, as yet, unknown, despite intensive research efforts. Research in this laboratory indicates that bilirubin and oxidative stress may be responsible by leading to formation of bilirubin oxidation products (BOXes), so we investigated changes in bilirubin concentration and oxidative stress in vitro, and in cerebral spinal fluid (CSF) from SAH patients. Non-SAH CSF, a source of heme oxygenase I (HO-1), and blood were incubated, and in vitro bilirubin production measured. Cerebrospinal fluid from SAH patients was collected, categorized using stimulation of vascular smooth muscle metabolism in vitro, and information obtained regarding occurrence of vasospasm in the patients. Cerebral spinal fluid was analyzed for hemoglobin, total protein and bilirubin, BOXes, malonyldialdehyde and peroxidized lipids (indicators of an oxidizing environment), and HO-1 concentration. The formation of bilirubin in vitro requires that CSF is present, as well as whole, non-anti-coagulated blood. Bilirubin, BOXes, HO-1, and peroxidized lipid content were significantly higher in CSF from SAH patients with vasospasm, compared with nonvasospasm SAH CSF, and correlated with occurrence of vasospasm. We conclude that vasospasm may be more likely in patients with elevated BOXes. The conditions necessary for the formation of BOXes are indeed present in CSF from SAH patients with vasospasm, but not CSF from SAH patients without vasospasm.
J Cereb Blood Flow Metab 2005 Aug
PMID:Bilirubin production and oxidation in CSF of patients with cerebral vasospasm after subarachnoid hemorrhage. 1578 34

The heme oxygenase (HO) enzymes catalyze the rate-limiting step in the breakdown of heme to iron, carbon monoxide, and biliverdin. A prior cell culture study demonstrated that deletion of HO-2, the isoform constitutively expressed in neurons, attenuated hemoglobin (Hb) neurotoxicity. The present study tested the hypothesis that HO-2 gene deletion is cytoprotective in a model of Hb toxicity in vivo. Stereotactic injection of 6 microL stroma-free Hb (SFHb) into the striatum significantly increased protein oxidation in wild-type mice at 24 to 72 h, as detected by an assay for carbonyl groups. At 72 h, carbonylation was increased 2.5-fold compared with that in the contralateral striatum. In HO-2 knockout mice, protein oxidation was not increased at 24 h, and was increased by only 1.7-fold at 72 h. Similarly, striatal lipid peroxidation, as detected by the malondialdehyde assay, was significantly greater in the SFHb-injected striata of wild-type mice than in knockout mice. Striatal cell viability, determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was 45.0%+/-6.3% of that in contralateral striata in wild-type mice at 72 h; it was increased to 85%+/-8% in knockouts. Heme oxygenase-2 gene deletion did not alter weight loss or mortality after SFHb injection. Baseline striatal HO-1 expression was similar in knockout and wild-type mice; induction after SFHb injection occurred more rapidly in the latter. These results suggest that HO-2 gene deletion protects striatal cells from the oxidative toxicity of Hb in vivo. Pharmacologic or genetic strategies that target HO-2 may be beneficial after central nervous system hemorrhage, and warrant further investigation.
J Cereb Blood Flow Metab 2005 Nov
PMID:Effect of targeted deletion of the heme oxygenase-2 gene on hemoglobin toxicity in the striatum. 1590 96

Intracranial bleeding is one of the most prominent aspects in the clinical diagnosis and prognosis of traumatic brain injury (TBI). Substantial amounts of blood products, such as heme, are released because of traumatic subarachnoid hemorrhages, intraparenchymal contusions, and hematomas. Despite this, surprisingly few studies have directly addressed the role of blood products, in particular heme, in the setting of TBI. Heme is degraded by heme oxygenase (HO) into three highly bioactive products: iron, bilirubin, and carbon monoxide. The HO isozymes, in particular HO-1 and HO-2, exhibit significantly different expression patterns and appear to have specific roles after injury. Developmentally, differences between the adult and immature brain have implications for endogenous protection from oxidative stress. The aim of this paper is to review recent advances in the understanding of heme regulation and metabolism after brain injury and its specific relevance to the developing brain. These findings suggest novel clinical therapeutic options for further translational study.
J Cereb Blood Flow Metab 2005 Nov
PMID:Heme regulation in traumatic brain injury: relevance to the adult and developing brain. 1591 48

We hypothesized that heme oxygenase (HO)-1, the inducible form of HO, represents an important defense against early oxidative injury in the traumatized spinal cord by stabilizing the blood-spinal cord barrier and limiting the infiltration of leukocytes. To test this hypothesis, we first examined the immunoexpression of HO-1 and compared barrier permeability and leukocyte infiltration in spinal cord-injured HO-1-deficient (+/-) and wild-type (WT, +/+) mice. Heme oxygenase was expressed in both endothelial cells and glia of the injured cord. Barrier disruption to luciferase and infiltration of neutrophils were significantly greater in the HO-1+/- than WT mice at 24 h postinjury (P<or=0.019 and =0.049, respectively). We next examined by Western immunoblots the generation of 4-hydroxynoneal (HNE) and malondialdehyde (MDA), major products of lipid peroxidation, in the injured epicenter. There was a significant increase in 10 kDa HNE- and MDA-modified proteins in the HO-1+/- as compared with WT mice (P=0.037 and 0.043, respectively). Finally, we compared the degradation of myelin basic protein (MBP), an indicator of white matter damage, in the HO-1+/- and WT mice by Western immunoblots. There was significantly greater degradation of MBP in the HO-1+/- compared with WT mice (P=0.049). Together, these findings show that HO-1 modulates oxidative stress and white matter injury in the acutely injured spinal cord. This modulation may be partially attributed to the ability of HO-1 to stabilize the blood-spinal cord barrier and limit neutrophil infiltration.
J Cereb Blood Flow Metab 2007 May
PMID:Heme oxygenase-1 stabilizes the blood-spinal cord barrier and limits oxidative stress and white matter damage in the acutely injured murine spinal cord. 1704 82


1 2 Next >>