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)

Carbon monoxide (CO) has been suggested as a novel messenger molecule in the brain. We now report on the cellular localization and hormone secretory function of a CO-producing constitutive heme oxygenase (HO-2) in mouse islets. Islet homogenates produced large amounts of CO which were suppressed dose-dependently by the HO inhibitor zincprotoporphyrin-IX (ZnPP-IX). We also show, for the first time, that glucose markedly stimulates the HO activity (CO production) in intact islets. A further potentiation was induced by the HO substrate hemin. Western blot showed that islet tissue expressed HO-2, and confocal microscopy revealed that HO-2 resided in insulin, glucagon, somatostatin, and pancreatic polypeptide cells. ZnPP-IX dose-dependently inhibited, whereas hemin enhanced, both insulin and glucagon secretion from glucose-stimulated islets. Stimulation or inhibition of CO production was accompanied by corresponding changes in islet cGMP levels. Exogenously applied CO stimulated insulin and glucagon release from isolated islets, whereas exogenous nitric oxide (NO) inhibited insulin and stimulated glucagon release. Islets stimulated by glucose or L-arginine displayed a marked increase in their NO-synthase (NOS) activity. Such an increase was suppressed by hemin, conceivably because NOS activity was inhibited by hemin-derived CO. Consequently, hemin enhanced L-arginine-induced insulin secretion. Insulin release stimulated by either hemin-derived CO or exogenous CO was strongly inhibited by the guanylate cyclase inhibitor ODQ, but it was unaffected by ZnPP-IX. Glucagon release induced by CO (but not by hemin) was inhibited by ODQ and partly inhibited by ZnPP-IX. We propose that the islets of Langerhans are equipped with a heme oxygenase-carbon monoxide pathway, which constitutes a novel regulatory system of physiological importance for the stimulation of insulin and glucagon release. This pathway is stimulated by glucose, is at least partly dependent on the cGMP system, and displays interaction with islet NOS activity.
 ...
PMID:Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study. 989 24

Recent reports indicate the presence of two carbon monoxide (CO)-inducing enzymes, heme oxygenase (HO)-1 and -2 in airway smooth muscle. Generally HO-2 is considered to be a constitutive enzyme associated with various neuronal structures, whereas HO-1 can be induced by several factors, including hypoxia. Recent functional data indicate that exogenous CO can induce bronchodilation via a NO-independent, cyclic GMP-related mechanism. The aim of the present study was to investigate the potential role of CO as an endogenously produced airway messenger using an in vivo model of airway hypoxia. HO-1 and HO-2-like immunoreactivities were seen in airway smooth muscle along the bronchus and in the respiratory epithelium. The staining for HO-1 was relatively weak but consistent in all animals investigated. In contrast, the HO-2 staining was intense at all locations. After hypoxic stimulation, the staining for HO-1 and HO-2 was equally intense, indicating an up-regulation of the HO-1 expression. In another set up, anaesthetized, ventilated guinea-pigs were given a continuous infusion of histamine to increase total pulmonary resistance (R1). Hypoxic stimulation, induced by inhalation of 180 breaths of pure nitrogen (N2), resulted in a subsequent reduction in R1. Pretreatment with Rp-8Br-cGMPs, a cyclic GMP antagonist abolished more than 75% of this reduction, whereas L-NAME, an antagonist of NO synthesis, was without effect. Zinc protoporphyrin-IX (ZnPP), an inhibitor of HO, mimicked the effects of Rp-8Br-cGMPS. In conclusion, the present findings suggest a possible role for CO in the hypoxic regulation of airway tone.
 ...
PMID:Carbon monoxide, a cyclic GMP-related messenger, involved in hypoxic bronchodilation in vivo. 1010 49

We have investigated the expression of heme oxygenase (HO) in the rat kidney and the effects of HO-dependent heme metabolites on the apical 70-pS K+ channel in the thick ascending limb (TAL). Reverse transcriptase-PCR (RT-PCR) and Western blot analyses indicate expression of the constitutive HO form, HO-2, in the rat cortex and outer medulla. Patch-clamping showed that application of 10 microM chromium mesoporphyrin (CrMP), an inhibitor of HO, reversibly reduced the activity of the apical 70-pS K+ channel, defined by NPo, to 26% of the control value. In contrast, addition of 10 microM magnesium protoporphyrin had no significant effect on channel activity. HO involvement in regulation of the apical 70-pS K+ channel of the TAL, was further indicated by the addition of 10 microM heme-L-lysinate, which significantly stimulated the channel activity in cell-attached patches by 98%. The stimulatory effect of heme on channel activity was also observed in inside-out patches in the presence of 0.5-1 mM reduced nicotinamide adenine dinucleotide phosphate. This was completely abolished by 10 microM CrMP, suggesting that a HO-dependent metabolite of heme mediated the effect. This was further supported by exposure of the cytosolic membrane of inside-out patches to a carbon monoxide-bubbled bath solution, which increased channel activity. Moreover, carbon monoxide completely abolished the effect of 10 microM CrMP on the channel activity. In contrast, 10 microM biliverdin, another HO-dependent metabolite of heme, had no effect. We conclude that carbon monoxide produced from heme via an HO-dependent metabolic pathway stimulates the apical 70-pS K+ channel in the rat TAL.
 ...
PMID:Carbon monoxide stimulates the apical 70-pS K+ channel of the rat thick ascending limb. 1019 68

The present study addresses the hypothesis that CO produced from endogenous heme oxygenase (HO) can dilate newborn cerebral arterioles. HO-2 protein was highly expressed in large and small blood vessels, as well as parenchyma, of newborn pig cerebrum. Topically applied CO dose-dependently dilated piglet pial arterioles in vivo over the range 10(-11)-10(-9) M (maximal response). CO-induced cerebrovascular dilation was abolished by treatment with the Ca2+-activated K+ channel inhibitors tetraethylammonium chloride and iberiotoxin. The HO substrate heme-L-lysinate also produced tetraethylammonium-inhibitable, dose-dependent dilation from 5 x 10(-8) to 5 x 10(-7) M (maximal). The HO inhibitor chromium mesoporphyrin blocked dilation of pial arterioles in response to heme-L-lysinate. In addition to inhibiting dilation to heme-L-lysinate, chromium mesoporphyrin also blocked pial arteriolar dilations in response to hypoxia but did not alter responses to hypercapnia or isoproterenol. We conclude that CO dilates pial arterioles via activation of Ca2+-activated K+ channels and that endogenous HO-2 potentially can produce sufficient CO to produce the dilation.
 ...
PMID:Carbon monoxide and cerebral microvascular tone in newborn pigs. 1033 Feb 49

Atherosclerosis is a major contributor to cardiovascular disease, and genetic disorders of lipoprotein metabolism are recognized risk factors in atherogenesis. The gaseous monoxides nitric oxide (NO) and carbon monoxide (CO), generated within the blood vessel wall, have been identified as important cellular messengers involved in the regulation of vascular smooth muscle tone. Microsomal heme oxygenases degrade heme to biliverdin and CO, and the cytosolic enzyme biliverdin reductase then catalyzes reduction of biliverdin to bilirubin, both powerful chain-breaking antioxidants. Two principal isozymes of heme oxygenase have been identified, a constitutive isoform HO-2 (M(r) approximately 34,000) and an inducible isoform HO-1 (M(r) approximately 32,000), which is expressed at a low basal level in vascular endothelial and smooth muscle cells and is induced by heavy metals, oxidative stress, inflammatory mediators and oxidized low density lipoproteins. Although NO and CO modulate intracellular cGMP levels, platelet aggregation and smooth muscle relaxation, CO has a much lower affinity for soluble guanylyl cyclase than NO. Decreased production or sensitivity to NO in atherosclerosis may be compensated for by an induction of HO-1, with bilirubin acting as a cellular antioxidant and CO as a vasodilator. This review examines the evidence that oxidized low density lipoproteins (LDL), hypoxia and pro-inflammatory cytokines induce HO-1 expression and activity in vascular endothelial and smooth muscle cells, and evaluates the anti-atherogenic potential of the heme oxygenase signalling pathway.
 ...
PMID:Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? 1034 38

We investigated whether the expression of heme oxygenase (HO) isozymes was related to the occurrence of ventricular fibrillation (VF) induced by ischemia/reperfusion in nondiabetic and diabetic myocardium. To study the role of HO-1 and HO-2 mRNA expression in VF, isolated hearts obtained from nondiabetic and 8-week diabetic rats were subjected to 30 min of ischemia followed by 2 h of reperfusion. Expression of HO-1 and HO-2 mRNA was studied in fibrillated and nonfibrillated myocardium using Northern blotting and reverse transcription polymerase chain reaction (RT-PCR). The effect of zinc protoporphyrin IX (Zn-PPIX), a potent inhibitor of HO activity, on HO activity was also studied in ischemic/reperfused hearts. Upon reperfusion, an expression of HO-1 was observed in nonfibrillated myocardium. HO-1 mRNA expression was significantly reduced in hearts showed VF. Zn-PPIX (5 microM) treatment reduced HO activity from its control values of 398+/-27 (in nondiabetics) and 370+/-20 pmol bilirubin/h (in diabetics) to 69+/-14 (in nondiabetics, p<.05) and 60+/-11 pmol bilirubin/h (in diabetics, p<.05), respectively, and all hearts, upon reperfusion, showed VF in both nondiabetic and diabetic subjects. HO-2 expression was unchanged in nonfibrillated and fibrillated myocardium. Postischemic function showed no correlation with the expression of these genes. Our data show that the mechanism(s) of ischemia/reperfusion-induced VF involves the downregulation of HO-1 mRNA and a reduction in HO activity. Furthermore, the mechanism(s) of VF at molecular level involving HO isozymes does not show a significant difference between nondiabetics and diabetics.
 ...
PMID:Heme oxygenase and cardiac function in ischemic/reperfused rat hearts. 1044 28

This study was performed to examine the differences in expression of heme oxygenase protein with age using immunocytochemistry. We compared the contents of HO-1 and HO-2 between young and aged rats using immunocytochemical methods. Stronger HO-1 expression was detected in the internal layer of the median eminence (ME) of aged than of young rats. Moreover, the cells expressing HO-1 were larger in the aged than the young animals. Electron microscopy indicated these cells with HO-1-like immunoreactivity (HO-1-LI) to be astrocytes. These findings suggested that the expression of HO-1 increased in the ME with age. The significance of this increased expression of HO-1 with age will be discussed briefly.
 ...
PMID:Expanded expression of heme oxygenase-1 (HO-1) in the hypothalamic median eminence of aged as compared with young rats: an immunocytochemical study. 1047 15

The neuromuscular junction is specialized for rapid transmission of electrical signals. Nitric oxide synthase (NOS) is concentrated at the junction, and NO modulates transmission and could influence signaling pathways. Increasing evidence suggests that carbon monoxide (CO) serves as a neurotransmitter, and heme oxygenase (HO), the enzyme that catalyzes the formation of CO, is often colocalized with NOS. Immunoreactivity for HO-2 was present at rat neuromuscular junctions of leg muscles and persisted in denervated muscle indicating the localization of the enzyme to the postsynaptic surface. In contrast, HO-2 immunoreactivity was absent from the en grappe and orbital en plaque endplates of extraocular muscle (EOM), while only the global en plaque endplates possessed HO-2 immunoreactivity. The difference between EOM and leg endplates may arise from EOM's unique physiology. The presence of HO-2 at neuromuscular junctions suggests CO could serve as a pre- and post-synaptic messenger.
 ...
PMID:Heme oxygenase-2 expression at rat neuromuscular junctions. 1051 79

The ultraviolet A (UVA, 320-400 nm) component of sunlight has the potential to generate an oxidative stress in cells and tissue so that antioxidants (both endogenous and exogenous) strongly influence the biological effects of UVA. The expression of several genes (including heme oxygenase-1, HO-1; collagenase; the CL100 phosphatase and the nuclear oncogenes, c-fos and c-jun) is induced following physiological doses of UVA to cells and this effect can be strongly enhanced by removing intracellular glutathione or enhancing singlet oxygen lifetime. We have observed that heme is released from microsomal heme-containing proteins by UVA and other oxidants and that activation of HO-1 expression by UVA correlates with levels of heme release. UVA radiation also leads to an increase in labile iron pools (either directly or via HO-1) and eventual increases in ferritin levels. The role of heme oxygenase in protection of skin fibroblasts is probably an emergency inducible defense pathway to remove heme liberated by oxidants. The slower increase in ferritin levels is an adaptive response which serves to keep labile iron pools low and thereby reduce Fenton chemistry and oxidant-induced chain reactions involving lipid peroxidation. In keratinocytes, the primary target of UVA radiation, heme oxygenase levels are constitutively high (because of HO-2 expression). Since there is a corresponding increase in basal levels of ferritin the epidermis appears to be well protected constitutively against the oxidative stress generated by UVA.
 ...
PMID:Redox regulation and oxidant activation of heme oxygenase-1. 1051 38

In mammals the rate-limiting step in heme catabolism is the heme oxygenase (HO) system. Two isozymes, HO-1 and HO-2, oxidatively cleave the substrate to form biliverdin, and the potential cellular messenger, CO; the chelated iron is released as the result of the tetrapyrrole ring opening. Biliverdin is subsequently reduced to bilirubin, an antioxidant, by biliverdin reductase. The aim of the present study was to investigate the involvement of HO-1, a heat shock/stress protein, in protection offered by the spin trap agent, N-tert-butyl-alpha-phenyl-nitrone (PBN), against kidney ischemia/reperfusion injury. For this, HO-1 expression and assessment of the parameters associated with tissue-oxidative injury were compared in the presence or absence of PBN pretreatment of rats (100 mg/kg i.p., 30 min) before the onset of 30-min ischemia. Twenty-four hours after reperfusion, Northern blot analysis showed an unprecedented approximately 37-fold increase in 1.8-kb HO-1 mRNA in PBN pretreated rat kidney; HO-2 mRNA levels did not increase. At 48 h, the levels of HO-1 mRNA remained nearly 14-fold higher than the control value. In the absence of PBN, the levels measured approximately 5- and 2-fold higher than control values at the 24- and 48-h intervals, respectively. PBN pretreatment also resulted in a most impressive increase in the levels of HO-1 protein as judged by Western blot analysis and measurement of enzyme activity at the 24-h time point. As detected by immunohistochemical analysis, PBN pretreatment caused an increase in HO-1 and biliverdin reductase-immunoreactive proteins in the cortex and in the outer stripe of the outer medulla. In the absence of PBN pretreatment, there was an intense immunostaining for HO-1 in the medullary rays, which corresponded with iron and lipid peroxidation staining of the region; these observations were not made with PBN-pretreated kidneys. Collectively, the findings are consistent with the likelihood that suprainduction of HO-1 gene expression protects the kidney from free radical-mediated injury by increasing the capacity to produce the potent cellular antioxidant bilirubin. We also suggest spin trap-mediated protection against ischemia/reperfusion injury is likely due to a sustained elevation of HO-1 gene expression by formation of stable radicals.
 ...
PMID:Spin trap (N-t-butyl-alpha-phenylnitrone)-mediated suprainduction of heme oxygenase-1 in kidney ischemia/reperfusion model: role of the oxygenase in protection against oxidative injury. 1052 16


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>