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 committed step in the biosynthesis of the phytochrome chromophore phytochromobilin involves the oxidative cleavage of heme by a heme oxygenase (HO) to form biliverdin IXalpha. Through positional cloning of the photomorphogenic mutant hy1, the Arabidopsis HO (designated AtHO1) responsible for much of phytochromobilin synthesis recently was identified. Using the AtHO1 sequence, we identified families of HO genes in a number of plants that cluster into two subfamilies (HO1- and HO2-like). The tomato (Lycopersicon esculentum) yg-2 and Nicotiana plumbaginifolia pew1 photomorphogenic mutants are defective in specific HO genes. Phenotypic analysis of a T-DNA insertion mutant of Arabidopsis HO2 revealed that the second HO subfamily also contributes to phytochromobilin synthesis. Homozygous ho2-1 plants show decreased chlorophyll accumulation, reduced growth rate, accelerated flowering time, and reduced de-etiolation. A mixture of apo- and holo-phyA was detected in etiolated ho2-1 seedlings, suggesting that phytochromobilin is limiting in this mutant, even in the presence of functional AtHO1. The patterns of Arabidopsis HO1 and HO2 expression suggest that the products of both genes overlap temporally and spatially. Taken together, the family of HOs is important for phytochrome-mediated development in a number of plants and that each family member may uniquely contribute to the phytochromobilin pool needed to assemble holo-phytochromes.
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PMID:The heme-oxygenase family required for phytochrome chromophore biosynthesis is necessary for proper photomorphogenesis in higher plants. 1140 95

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

The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS) systems display notable similarities as well as differences. HO and NOS are both oxidative enzymes using NADPH as an electron donor. The constitutive forms of the enzyme are differentially activated, with calcium entry stimulating NOS by binding to calmodulin, whereas calcium entry activates protein kinase C to phosphorylate and activate HO2. Although both NO and carbon monoxide (CO) stimulate soluble guanylyl cyclase to form cGMP, NO also S-nitrosylates selected protein targets. Both involve constitutive and inducible biosynthetic enzymes. However, functions of the inducible forms are virtual opposites. Macrophage-inducible NOS generates NO to kill other cells, whereas HO1 generates bilirubin to exert antioxidant cytoprotective effects and also provides cytoprotection by facilitating iron extrusion from cells. The neuronal form of HO, HO2, is also cytoprotective. Normally, neural NO in the brain seems to exert some sort of behavioral inhibition. However, excess release of NO in response to glutamate's N-methyl-d-aspartate receptor activation leads to stroke damage. On the other hand, massive neuronal firing during a stroke presumably activates HO2, leading to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO inhibition by mutant forms of amyloid precursor protein may mediate neurotoxicity in Familial Alzheimer's Disease. NO and CO both appear to be neurotransmitters in the brain and peripheral autonomic nervous system. They also are physiologic endothelial-derived relaxing factors for blood vessels. In the gastrointestinal pathway, NO and CO appear to function as coneurotransmitters, both stimulating soluble guanylyl cyclase to cause smooth muscle relaxation.
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PMID:Neural roles for heme oxygenase: contrasts to nitric oxide synthase. 1157 59

SD rats were pretreated with whole body hyperthermia (rectal 42 degrees C) for 15 min. The level of calcitonin gene-related peptide (CGRP) in plasma, and alpha- and beta-CGRP mRNA as well as heme oxygenease-1 and heme oxygenase-2 mRNA in dorsal root ganglia were determined by radioimmunoassay and semi-quantitative reverse-transcription polymerase chain reaction, respectively. Heat stress induced only the expression of alpha-CGRP or heme oxygenease-1 but not beta-CGRP or heme oxygenase-2 mRNA, and the release of CGRP and induction of alpha-CGRP mRNA expression were abolished by pretreatment with Zinc protoporphyrin IX, the heme oxygenase inhibitor, or methylene blue, the inhibitor of soluble guanylate cyclase. These results indicate that induction of alpha-CGRP mRNA expression in rat DRG by heat stress involves the heme oxygenase-1/carbon monoxide pathway.
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PMID:Induction of alpha-calcitonin gene-related peptide mRNA expression in rat dorsal root ganglia by heat stress involves the heme oxygenase-1/carbon monoxide pathway. 1203 Aug 15

The role of heme oxygenase reaction products in modulation of stomach fundus excitability was studied. The presence of constitutive heme oxygenase 2 was verified in myenteric ganglia by immunohistochemistry. The role of inducible heme oxygenase isoenzyme was investigated after invivo treatment of animals with CoCl2 (80 mg kg-1 b.w) injected subcutaneously 24 h before they were killed. This treatment resulted in increased production of bilirubin and positive staining for the inducible isoform in stomach smooth muscle and vast induction in the liver. In both control and treated animals haemin, applied to the bath as a substrate of heme oxygenase caused significant decrease of prostaglandin F2alpha-induced tone, and ameliorated the relaxatory response of the fundic strips to electrical field stimulation. Both effects were antagonized by Sn-protoporphyrin IX, competitive heme oxygenase inhibitor, and were found to be neuronally dependent. In single freshly isolated smooth muscle cells from control animals haemin caused a concentration-dependent increase of the whole cell K+ currents, which was not affected by Sn-protoporphyrin IX, cyclic guanosine monophosphate (cGMP)-dependent protein kinase or guanylyl cyclase antagonists, but was reversed by various antioxidants and abolished by an NO scavenger. In cells from treated animals the K+ current increasing effect of haemin did not depend on the presence of antioxidants, but was abolished by protein kinase G and guanylyl cyclase inhibitors, depletors of intracellular Ca2+ pools or Sn-protoporphyrin IX. Biliverdin did not affect contraction or ionic currents. Thus, this is the first study demonstrating that heme oxygenase is an inducible enzyme in guinea-pigs, which exerts a modulatory role on gastric smooth muscle excitability via carbon monoxide production.
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PMID:Induction of heme oxygenase in guinea-pig stomach: roles in contraction and in single muscle cell ionic currents. 1216 69

The haem oxygenase (HO) enzyme catalyses the oxidation of haem to biliverdin IX alpha, CO and Fe(2+), and performs a wide variety of roles in Nature, including degradation of haem from haemoglobin, iron acquisition and phycobilin biosynthesis. In plants, HOs are required for the synthesis of the chromophore of the phytochrome family of photoreceptors. There are four HO genes in the Arabidopsis genome. Analysis of a mutant deficient in HO1 (the hy1 mutant) has demonstrated that this plastid-localized protein is the major HO in the phytochrome chromophore synthesis pathway. HO2 may also have a minor role in this pathway, but our understanding of the divergent roles of this small gene family is still far from complete.
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PMID:Making light of it: the role of plant haem oxygenases in phytochrome chromophore synthesis. 1219 46

In porcine gastric fundus, we have investigated the colocalization of the bile pigment biosynthetic enzymes heme oxygenase-2 and biliverdin reductase with neuronal nitric oxide synthase (nNOS), the effect of carbon monoxide (CO) on fundic circular smooth muscle and the possible modulatory effect of the bile pigments biliverdin and bilirubin on CO-mediated relaxations and on nitrergic relaxation. Heme oxygenase-2 and biliverdin reductase immunoreactivity was present in all nNOS containing myenteric neurons. CO induced a concentration-dependent relaxation of fundic circular smooth muscle strips, which was completely blocked by the specific guanylate cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), biliverdin and bilirubin strongly enhanced the amplitude of the CO-induced relaxation. Tin protoporphyrin had no effect on electrically induced nitrergic relaxation, but spectrophotometric analysis learned that incubation of porcine gastric fundus circular muscle strips with tin protoporphyrin did not influence heme oxygenase activity. In conclusion, our data suggest that nitrergic neurons in the pig gastric fundus are able to produce biliverdin and bilirubin, and that these agents potentiate the relaxant effect of CO, which is formed concomitantly with biliverdin by heme oxygenase-2.
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PMID:Investigation of the potential modulatory effect of biliverdin, carbon monoxide and bilirubin on nitrergic neurotransmission in the pig gastric fundus. 1246 64

Carbon monoxide (CO) is proposed as a physiological messenger. CO activates cGMP and has a direct effect on potassium channels. Both actions of CO lead to hyperpolarization of a cell's resting membrane potential, suggesting that CO may function as a hyperpolarizing factor, although direct evidence is still lacking. Here we take advantage of the known membrane potential gradient that exists in the muscle layers of the gastrointestinal tract to determine whether CO is an endogenous hyperpolarizing factor. We find that heme oxygenase-2-null mice have depolarized smooth muscle cells and that the membrane potential gradient in the gut is abolished. Exogenous CO hyperpolarizes the membrane potential. Regions of the canine gastrointestinal tract that are more hyperpolarized generate more CO and have higher heme oxygenase activity than more depolarized regions. Our results suggest that CO is a critical hyperpolarizing factor required for the maintenance of intestinal smooth muscle membrane potential and gradient.
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PMID:A major role for carbon monoxide as an endogenous hyperpolarizing factor in the gastrointestinal tract. 1283 17

Heme oxygenase is the rate-limiting enzyme in the catabolism of heme to carbon monoxide, bilirubin and free iron. Many cell types express heme oxygenase-2 constitutively while heme oxygenase-1 is induced at sites of inflammation and oxidative stress. In systemic blood vessels, carbon monoxide may have an important homeostatic role where, like its better-studied counterpart nitric oxide, it is emerging as a vasodilator and an inhibitor of proliferation. However, much less is known regarding the role of heme oxygenase and carbon monoxide in the pulmonary circulation where vascular responses are very different. Here, using primary cultures of human pulmonary artery smooth muscle cells, we present novel data showing that this cell type expresses heme oxygenase-2 constitutively and, in the presence of oxidants, can induce heme oxygenase-1. We also show that the carbon monoxide-releasing molecule, tricarbonyldichlororuthenium (II) dimer, potently and profoundly inhibits proliferation of human pulmonary artery smooth muscle cells. Pulmonary hypertension is a disease characterised by abnormal vascular smooth muscle cell growth and remodelling of the pulmonary vasculature. Our observations support the growing evidence that the heme oxygenase/carbon monoxide system may play a role in the pathology of pulmonary hypertension.
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PMID:Heme oxygenase is expressed in human pulmonary artery smooth muscle where carbon monoxide has an anti-proliferative role. 1289 30

In a prior study, we observed that heme oxygenase-2 gene deletion protected murine cortical neurons from heme-mediated injury. In the course of these studies, constitutive HO-2 expression was observed in astrocyte cultures. The present study tested the hypothesis that astrocytes lacking the HO-2 gene would be less vulnerable to heme. Contrary to this hypothesis, gene deletion resulted in a 50-75% increase in cell death after 6h exposure to 30 or 60microM hemin, as measured by LDH release. A similar effect was observed when cell viability was assessed with the MTT assay. HO-2 gene deletion did not alter cellular expression of HO-1. The increased sensitivity of knockout astrocytes to hemin was reversed by increasing HO-1 expression by adenoviral gene transfer. These results suggest that heme oxygenase protects astrocytes from heme-mediated oxidative injury and highlight the disparate effect of HO in neurons and astrocytes.
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PMID:Heme oxygenase-2 gene deletion increases astrocyte vulnerability to hemin. 1511 Jul 57


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