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)

The enzymatic action of heme oxygenase yields carbon monoxide, biliverdin and iron. Carbon monoxide is implicated in many physiological processes, including the regulation of vascular tissue contractility and apoptosis. By stimulating the soluble guanylyl cyclase (sGC)/cGMP pathway and activating K channels in vascular smooth muscle cells (SMCs), carbon monoxide relaxes vascular tissues under physiological conditions. Altered metabolism and functions of carbon monoxide have been linked to the pathogenesis and maintenance of hypertension. The expression and activity of heme oxygenase-1, sGC and cGMP in vascular SMCs are associated with different stages of development of hypertension in spontaneously hypertensive rats (SHRs). The importance of altered heme oxygenase-2 expression in vascular tissues in hypertension remains unclear. Increased vascular contractility, unbalanced cellular apoptosis and proliferation in the vascular wall, increased oxidative stress, and the altered interaction of carbon monoxide and nitric oxide are among the consequences of heme oxygenase/carbon monoxide system dysfunction in hypertension. Acute application of pharmacological inducers to upregulate the expression of heme oxygenase-1 or the use of gene delivery method to overexpress heme oxygenase-1 decreases blood pressure in young SHRs and other animal models of hypertension. These blood pressure-decreasing effects are annulled by metalloporphyrins. In adult SHRs, the heme oxygenase/carbon monoxide system appears to be normalized as a compensatory reaction. To date, acute manipulation of the expression of heme oxygenase-1 has not been successful in decreasing blood pressure in adult SHRs. In conclusion, abnormality of the heme oxygenase/carbon monoxide system has a critical role in the pathogenesis of hypertension, and novel therapeutic approaches should be pursued to achieve selective improvement in the function of this system in hypertension.
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PMID:Carbon monoxide and hypertension. 1516 36

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

In the normal mammalian CNS, heme oxygenase-2 (HO-2) is constitutively, abundantly, and fairly ubiquitously expressed, whereas heme oxygenase-1 (HO-1) mRNA and protein are confined to small populations of scattered neurons and neuroglia. Unlike ho-2, the ho-1 gene in neural (and many systemic) tissues is exquisitely sensitive to upregulation by a host of pro-oxidant and other noxious stimuli. In Alzheimer disease, HO-1 immunoreactivity is significantly augmented in neurons and astrocytes of the hippocampus and cerebral cortex relative to age-matched, nondemented controls and colocalizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO-1 decorates Lewy bodies of affected dopaminergic neurons and is highly overexpressed in astrocytes residing within the substantia nigra. The ho-1 gene is also upregulated in glial cells within multiple sclerosis plaques; in the vicinity of human cerebral infarcts, hemorrhages, and contusions; and in various other degenerative and nondegenerative human CNS disorders. The products of the heme oxygenase reaction, free ferrous iron, carbon monoxide, and biliverdin/bilirubin, are all biologically active molecules that may profoundly influence tissue redox homeostasis under a wide range of pathophysiological conditions. Evidence adduced from whole animal and in vitro studies indicates that enhanced HO-1 activity may either ameliorate or exacerbate neural injury, effects likely contingent upon the specific model employed, the duration and intensity of HO-1 induction, and the chemistry of the local redox microenvironment. HO-1 hyperactivity also promotes mitochondrial sequestration of nontransferrin iron in oxidatively challenged astroglia and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in aging and degenerating human neural tissues.
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PMID:Heme oxygenase expression in human central nervous system disorders. 1554 18

Hemin (10 microM) and carbon monoxide (CO) increased iberiotoxin-blockable IKCa in portal vein smooth muscle cells. CO-induced IKCa activation was abolished by 10 microM ODQ, 10 microM cyclopiazonic acid and 1 microM KT5823. The hemin-induced effect on IKCa was abolished by pretreatment with Sn-protoporphyrin IX, a heme oxygenase inhibitor and Fe2+ chelator but was insensitive to inhibitors of soluble guanylate cyclase (GC) and cGMP-dependent protein kinase (PKG). There was no effect of hemin on IKCa in the presence of 3 microM dithiotreitol into the bath or 3 mM glutathione into the pipette solution. Superoxide dismutase (1000 U/ml) or catalase (3000 U/ml) added into the pipette solution also abolished the effect of hemin on IKCa in this tissue. Additionally, 10 microM hemin could not influence IKCa in Ca2+-free external solution or in the presence of 30 microM SKF 95356. It was concluded that CO increases IKCa via its "conventional" signaling pathway, which involves soluble GC and PKG activation and subsequent stimulation of sarcoplasmic reticulum Ca2+ pump activity resulting in Ca2+-dependent activation of IKCa due to the accumulation of Ca2+ into the space near the plasma membrane. On the other hand, internally produced CO could not yield the same IKCa increase, while Fe2+ derived from heme oxygenase 2-dependent degradation of hemin in portal vein smooth muscle cells gives rise to reactive oxygen species namely hydroxyl and superoxide radicals. Both radicals are responsible for the SKF 95356-sensitive non-selective cation channel activation, the Ca2+ influx and the subsequent increase of Ca2+ concentration near the plasma membrane that augments the KCa channel activity.
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PMID:Heme oxygenase-2 products activate IKCa: role of CO and iron in guinea pig portal vein smooth muscle cells. 1554 71

Polymers of cell-free hemoglobin have been designed for clinical use as oxygen carriers, but limited information is available regarding their effects on vascular regulation. We tested the hypothesis that the contribution of heme oxygenase (HO) to acetylcholine-evoked dilation of pial arterioles is upregulated 2 days after polymeric hemoglobin transfusion. Dilator responses to acetylcholine measured by intravital microscopy in anesthetized cats were blocked by superfusion of the HO inhibitor tin protoporphyrin-IX (SnPPIX) in a group that had undergone exchange transfusion with hemoglobin 2 days earlier but not in surgical sham and albumin-transfused groups. However, immunoblots from cortical brain homogenates did not reveal changes in expression of the inducible isoform HO1 or the constitutive isoform HO2 in the hemoglobin-transfused group. To test whether the inhibitory effect of SnPPIX was present acutely after hemoglobin transfusion, responses were measured within an hour of completion of the exchange transfusion. In control and albumin-transfused groups, acetylcholine responses were unaffected by SnPPIX but were blocked by addition of the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine (l-NNA) to the superfusate. In hemoglobin-transfused groups, the acetylcholine response was blocked by either SnPPIX or l-NNA alone. The effect of another HO inhibitor, chromium mesoporphyrin (CrMP), was tested on ADP, another endothelial-dependent dilator, in anesthetized rats. Pial arteriolar dilation to ADP was unaffected by CrMP in controls but was attenuated 62% by CrMP in rats transfused with hemoglobin. It is concluded that 1) polymeric hemoglobin transfusion acutely upregulates the contribution of HO to acetylcholine-induced dilation of pial arterioles in cats, 2) this upregulation persists 2 days after transfusion when 95% of the hemoglobin is cleared from the circulation, and 3) this acute upregulation of HO signaling is ubiquitous in that similar effects were observed with a different endothelial-dependent agonist (i.e., ADP) in a another species (rat).
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PMID:Dependence of acetylcholine and ADP dilation of pial arterioles on heme oxygenase after transfusion of cell-free polymeric hemoglobin. 1621 47

Heme oxygenase consists of two structurally related isozymes, heme oxygenase-1 and and heme oxygenase-2, each of which cleaves heme to form biliverdin, iron and carbon monoxide. Expression of heme oxygenase-1 is increased or decreased depending on cellular microenvironments, whereas little is known about the regulation of heme oxygenase-2 expression. Here we show that hypoxia (1% oxygen) reduces the expression levels of heme oxygenase-2 mRNA and protein after 48 h of incubation in human cell lines, including Jurkat T-lymphocytes, YN-1 and K562 erythroleukemia, HeLa cervical cancer, and HepG2 hepatoma, as judged by northern blot and western blot analyses. In contrast, the expression level of heme oxygenase-1 mRNA varies under hypoxia, depending on the cell line; it was increased in YN-1 cells, decreased in HeLa and HepG2 cells, and remained undetectable in Jurkat and K562 cells. Moreover, heme oxygenase-1 protein was decreased in YN-1 cells under the conditions used, despite the induction of heme oxygenase-1 mRNA under hypoxia. The heme oxygenase activity was significantly decreased in YN-1, K562 and HepG2 cells after 48 h of hypoxia. To explore the mechanism for the hypoxia-mediated reduction of heme oxygenase-2 expression, we showed that hypoxia shortened the half-life of heme oxygenase-2 mRNA (from 12 h to 6 h) in YN-1 cells, without affecting the half-life of heme oxygenase-1 mRNA (9.5 h). Importantly, the heme contents were increased in YN-1, HepG2 and HeLa cells after 48 h of incubation under hypoxia. Thus, the reduced expression of heme oxygenase-2 may represent an important adaptation to hypoxia in certain cell types, which may contribute to the maintenance of the intracellular heme level.
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PMID:Hypoxia reduces the expression of heme oxygenase-2 in various types of human cell lines. A possible strategy for the maintenance of intracellular heme level. 1678 41

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 aims of this study were to quantify the change in resting membrane potential (RMP) across the thickness of the circular muscle layer in the mouse and human small intestine and to determine whether the gradient in RMP is dependent on the endogenous production of carbon monoxide (CO). Conventional sharp glass microelectrodes were used to record the RMPs of circular smooth muscle cells at different depths in the human small intestine and in wild-type, HO2-KO, and W/W(V) mutant mouse small intestine. In the wild-type mouse and human intestine, the RMP of circular smooth muscle cells near the myenteric plexus was -65.3 +/- 2 mV and -58.4 +/- 2 mV, respectively, and -60.1 +/- 2 mV and -49.1 +/- 1 mV, respectively, in circular smooth muscle cells at the submucosal border. Oxyhemoglobin (20 microM), a trapping agent for CO, and chromium mesoporphyrin IX, an inhibitor of heme oxygenase, abolished the transwall gradient. The RMP gradients in mouse and human small intestine were not altered by N(G)-nitro-l-arginine (200 microM). No transwall RMP gradient was found in HO2-KO mice and W/W(V) mutant mice. TTX (1 microM) and 1H-[1,2,4-]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM) had no effect on the RMP gradient. These data suggest that the gradient in RMP across the thickness of the circular muscle layer of mouse and human small intestine is CO dependent.
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PMID:Membrane potential gradient is carbon monoxide-dependent in mouse and human small intestine. 1751 Jan 99

Kidney disease is a frequent consequence of heavy metal exposure and renal anemia occurs secondarily to the progression of kidney deterioration into chronic disease. In contrast, little is known about effects on kidney of chronic exposure to low levels of depleted uranium (DU). Study was performed with rats exposed to DU at 40 mg/l by chronic ingestion during 9 months. In the present work, a approximately 20% reduction in red blood cell (RBC) count was observed after DU exposure. Hence, three hypotheses were tested to determinate origin of RBC loss: (1) reduced erythropoiesis, (2) increased RBC degradation, and/or (3) kidney dysfunction. Erythropoiesis was not reduced after exposure to DU as revealed by erythroid progenitors, blood Flt3 ligand and erythropoietin (EPO) blood and kidney levels. Concerning messenger RNA (mRNA) and protein levels of spleen iron recycling markers from RBC degradation (DMT1 [divalent metal transporter 1], iron regulated protein 1, HO1, HO2 [heme oxygenase 1 and 2], cluster of differentiation 36), increase in HO2 and DMT1 mRNA level was induced after chronic exposure to DU. Kidneys of DU-contaminated rats had more frequently high grade tubulo-interstitial and glomerular lesions, accumulated iron more frequently and presented more apoptotic cells. In addition, chronic exposure to DU induced increased gene expression of ceruloplasmin (x12), of DMT1 (x2.5), and decreased mRNA levels of erythropoietin receptor (x0.2). Increased mRNA level of DMT1 was associated to decreased protein level (x0.25). To conclude, a chronic ingestion of DU leads mainly to kidney deterioration that is probably responsible for RBC count decrease in rats. Spleen erythropoiesis and molecules involved in erythrocyte degradation were also modified by chronic DU exposure.
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PMID:Renal anemia induced by chronic ingestion of depleted uranium in rats. 1837 46

Carbon monoxide derived from heme oxygenase (HO) may participate in cerebrovascular regulation under specific circumstances. Previous work has shown that HO contributes to feline pial arteriolar dilation to acetylcholine after transfusion of a cell-free polymeric hemoglobin oxygen carrier. The role of constitutive HO2 in the pial arteriolar dilatory response to acetylcholine was determined by using 1) HO2-null mice (HO2-/-), 2) the HO inhibitor tin protoporphyrin IX (SnPPIX), and 3) 4,5,6,7-tetrabromobenzotriazole (TBB), an inhibitor of casein kinase-2 (CK2)-dependent phosphorylation of HO2. In anesthetized mice, superfusion of a cranial window with SnPPIX decreased arteriolar dilation produced by 10 microM acetylcholine by 51%. After partial polymeric hemoglobin exchange transfusion, the acetylcholine response was normal but was reduced 72% by SnPPIX and 95% by TBB. In HO2-/- mice, the acetylcholine response was modestly reduced by 14% compared with control mice and was unaffected by SnPPIX. After hemoglobin transfusion in HO2-/- mice, acetylcholine responses were also unaffected by SnPPIX and TBB. In contrast, nitric oxide synthase inhibition completely blocked the acetylcholine responses in hemoglobin-transfused HO2-/- mice. We conclude 1) that HO2 activity partially contributes to acetylcholine-induced pial arteriolar dilation in mice, 2) that this contribution is augmented in the presence of a plasma-based hemoglobin polymer and appears to depend on a CK2 kinase mechanism, 3) that nitric oxide synthase activity rather than HO1 activity contributes to the acetylcholine reactivity in HO2-/- mice, and 4) that plasma-based polymeric hemoglobin does not scavenge all of the nitric oxide generated by cerebrovascular acetylcholine stimulation.
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PMID:Role of heme oxygenase-2 in pial arteriolar response to acetylcholine in mice with and without transfusion of cell-free hemoglobin polymers. 1849 34


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