Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated levels of carbon monoxide (CO) are found in the exhaled breath of patients with inflammatory diseases such as asthma and cystic fibrosis. Endogenous CO is derived from heme oxygenase (HO) (EC 1.14.99.3), which catabolizes heme-producing CO and biliverdin. There are three isoforms of HO: HO-1 is inducible by inflammatory cytokines and oxidants, including nitric oxide (NO), whereas HO-2 and HO-3 are expressed constitutively. Primary airway epithelial cells were treated with either 50 ng/ml interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma (cytomix), or the NO donor NOC-18 for up to 24 h. Cytomix-induced HO-1 expression peaked at 4 h, returning to baseline by 24 h, whereas HO-2 expression remained unchanged. This increase in HO-1 expression could not be explained by an increase in NO production as inducible NO synthase expression increased between 12 and 24 h. However, the NO donor NOC-18 (500 microM) increased HO-1 expression twofold and HO activity 25-fold, whereas cytomix treatment increased HO activity eightfold. NO induction of HO-1 was not mediated via guanylyl cyclase and was not attenuated by 1 microM dexamethasone, although dexamethasone increased HO-2 protein. Therefore, airway epithelial cells express HO-2 and can express HO-1; thus, the epithelium may be a source of increased CO in airway diseases.
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PMID:Expression of heme oxygenase in human airway epithelial cells. 1124 28

We investigated, by a combined in vivo and in vitro approach, the temporal changes of islet nitric oxide synthase (NOS)-derived nitric oxide (NO) and heme oxygenase (HO)-derived carbon monoxide (CO) production in relation to insulin and glucagon secretion during acute endotoxemia induced by lipopolysaccharide (LPS) in mice. Basal plasma glucagon, islet cAMP and cGMP content after in vitro incubation, the insulin response to glucose in vivo and in vitro, and the insulin and glucagon responses to the adenylate cyclase activator forskolin were greatly increased after LPS. Immunoblots demonstrated expression of inducible NOS (iNOS), inducible HO (HO-1), and an increased expression of constitutive HO (HO-2) in islet tissue. Immunocytochemistry revealed a marked expression of iNOS in many beta-cells, but only in single alpha-cells after LPS. Moreover, biochemical analysis showed a time dependent and markedly increased production of NO and CO in these islets. Addition of a NOS inhibitor to such islets evoked a marked potentiation of glucose-stimulated insulin release. Finally, after incubation in vitro, a marked suppression of NO production by both exogenous CO and glucagon was observed in control islets. This effect occurred independently of a concomitant inhibition of guanylyl cyclase. We suggest that the impairing effect of increased production of islet NO on insulin secretion during acute endotoxemia is antagonized by increased activities of the islet cAMP and HO-CO systems, constituting important compensatory mechanisms against the noxious and diabetogenic actions of NO in endocrine pancreas.
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PMID:Evaluation of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia. 1128 38

Previous investigations have shown that NO-producing nitric oxide synthase (NOS)-1 and CO-generating heme oxygenase (HO-2) are associated with the sarcolemma of skeletal muscle fibers in many mammalian species. Despite numerous roles ascribed to NO and possibly also CO in skeletal muscle, a specific receptor for both gases has hitherto not been found in myofibers. Therefore, in the present work the appearance of the alpha1, beta1 and beta2 subunits of soluble guanylate cyclase (sGC), the most commonly known receptor for NO and potentially also CO, was analysed in mammalian skeletal muscles using immunoblotting and immunohistochemistry. Immunoblotting with an antibody against the beta1 subunit of sGC revealed a band of 70 kDa corresponding to the molecular weight of this protein. Immunohistochemistry with antibodies against the alpha1, beta1 and beta2 sGC subunits showed that the larger part of positivity was present in the sarcolemma region of skeletal muscle fibers and colocalized with NOS-1 mainly in type II myofibers and with HO-2 in type I and type II myofibers. For the first time, sarcolemmal association of sGC and its colocalization with NOS-1 generating the sGC-activator NO and with HO-2 producing the potential sGC upregulator CO have been demonstrated in the present study. These results enable a better understanding of the role of NO and CO in myofibers and suggest a so far unknown molecular mechanism for the interaction of sGC with the sarcolemma.
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PMID:Association of soluble guanylate cyclase with the sarcolemma of mammalian skeletal muscle fibers. 1148 73

Spinal cord tissue contains two enzyme systems capable of producing monoxide gases which in turn are linked to the stimulation of soluble guanylate cyclase, nitric oxide synthase (NOS) which produces NO and heme oxygenase (HO) which produces CO. Reports from several laboratories link these two enzyme systems to pain of inflammatory and neuropathic etiologies. Additional studies have demonstrated that the activation of the NOS system by morphine limits the spinal analgesic action of this drug. In this study we first employed the hot plate model of pain to demonstrate that the NOS inhibitor L-NAME and the HO inhibitor Sn-P potentiate the analgesic actions of intrathecally administered morphine while having no intrinsic analgesic action at the doses used. We then determined that L-NAME loses its ability to potentiate morphine in nNOS null-mutant mice, while Sn-P no longer potentiates morphine in mice lacking a functional HO-2 gene. The intrathecal injection of the cGMP analog 8-Br cGMP caused hyperalgesia in the hot plate assay. Focusing on the possible involvement of cGMP metabolism, we documented that morphine stimulates cGMP production in a spinal cord slice model in a concentration dependent and naloxone reversible manner. Both L-NAME and Sn-P were potent inhibitors of morphine-stimulated cGMP production. Buffer containing either CO or the NO donor compound SNAP stimulated cGMP production as well. In spinal cord slices from either nNOS or HO-2 null-mutant animals morphine did not stimulate cGMP production. Taken together our data suggest that spinal monoxide generation modifies the acute analgesic actions of morphine.
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PMID:Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. 1168 80

Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. HO exists as constitutive (HO-2, HO-3) and inducible isoforms (HO-1), the latter which responds to regulation by multiple stress-stimuli. HO-1 confers protection in vitro and in vivo against oxidative cellular stress. Although the redox active compounds that are generated from HO activity (i.e. iron, biliverdin-IXalpha, and bilirubin-IXa) potentially modulate oxidative stress resistance, increasing evidence points to cytoprotective roles for CO. Though not reactive, CO regulates vascular processes such as vessel tone, smooth muscle proliferation, and platelet aggregation, and possibly functions as a neurotransmitter. The latter effects of CO depend on the activation of guanylate cyclase activity by direct binding to the heme moiety of the enzyme, stimulating the production of cyclic 3':5'-guanosine monophosphate. CO potentially interacts with other intracellular hemoprotein targets, though little is known about the functional significance of such interactions. Recent progress indicates that CO exerts novel anti-inflammatory and anti-apoptotic effects dependent on the modulation of the p38 mitogen activated protein kinase (MAPK)-signaling pathway. By virtue of these effects, CO confers protection in oxidative lung injury models, and likely plays a role in HO-1 mediated tissue protection.
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PMID:Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. 1216 41

Heme Oxygenase is the rate-limiting enzyme in the degradation of heme into carbon monoxide (CO), iron and bilirubin. To date, three heme oxygenase isozymes have been identified: HO-1, HO-2 and HO-3. While HO-1 is structurally different from its counterparts, HO-2 and HO-3 are very similar (90% homology), with HO-3 being a poor heme catalyst. Of the three isozymes, HO-1 is believed to be the only inducible form. Constitutively expressed HO-2 has been identified in several organs including kidney and vascular smooth muscle, with the most abundant sources (and activity) being in the liver, brain, spleen and testes. Within the normal liver, HO-2 is constitutively expressed within hepatocytes, Kupffer cells, endothelial cells and Ito cells. Until recently, products of the HO reaction were regarded as potentially toxic waste destined only for excretion. However, this view is changing as evidence suggests that HO activity plays an important protective role against cellular stress during inflammatory diseases. Biliverdin is reduced to bilirubin, which has been shown to possess potent antioxidative properties. CO, which is produced in equimolar concentrations to biliverdin and ferrous iron during heme oxidation by HO, may function as a second messenger stimulating soluble guanylate cyclase (sGC) and regulating vascular tone in combination with the free radical gas NO. CO may also possess anti-inflammatory properties such as the capacity to inhibit platelet aggregation, or the expression of pro-inflammatory cytokines. Recently, it has been shown that CO regulates bile formation and bile flow. We review the functional role of HO in liver and the potential application of HO-1 in therapeutic approaches to the treatment of inflammation.
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PMID:The heme oxygenase system: its role in liver inflammation. 1287 Oct 38

Heme oxygenase (HO) degrades heme to carbon monoxide (CO), ferrous ions, and the bile pigment biliverdin, which is subsequently reduced to the other important bile pigment, bilirubin, by biliverdin reductase. Fe2+ liberated from the heme molecule upregulates ferritin production, and bile pigments are potent endogenous antioxidants. The HO enzyme exists in three isophorms: HO-1 is expressed at low levels under physiological conditions, but is induced by numerous factors, including oxidative stress, inflammation, nitric oxide, an elevated level of substrate, and hypoxia. HO-2 is a constitutive enzyme involved in the baseline production of CO in the cardiovascular and nervous systems, whereas HO-3 is also ubiquitously expressed, but possesses low catalytic activity. Like nitric oxide, CO activates soluble guanylate cyclase and elevates cGMP in target tissues, which dilates blood vessels. It also does this by directly activating potassium channels in vascular smooth muscle cells. In addition, CO inhibits platelet aggregation and proliferation of vascular smooth muscle cells, inhibits apoptosis, and stimulates angiogenesis. Both deficiency, and excess of HO-1 may be involved in the pathogenesis of arterial hypertension. Induction of HO-1 attenuates atherosclerosis and myocardial ischemia-reperfusion injury. Pharmacological and genetic induction of HO-1 as well as the delivery of exogenous CO are promising therapeutic strategies for the treatment of cardiovascular diseases.
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PMID:[Heme oxygenase and carbon monoxide in the physiology and pathology of the cardiovascular system]. 1506 78

The heart constitutively expresses heme oxygenase (HO)-2, which catabolizes heme-containing proteins to produce biliverdin and carbon monoxide (CO). The heart also contains many possible substrates for HO-2 such as heme groups of myoglobin and cytochrome P-450s, which potentially could be metabolized into CO. As a result of observations that CO activates guanylyl cyclase and induces vascular relaxation and that HO appears to confer protection from ischemic injury, we hypothesized that the HO-CO pathway is involved in ischemic vasodilation in the coronary microcirculation. Responses of epicardial coronary arterioles to ischemia (perfusion pressure approximately 40 mmHg; flow velocity decreased by approximately 50%; dL/dt reduced by approximately 60%) were measured using stroboscopic fluorescence microangiography in 34 open-chest anesthetized dogs. Ischemia caused vasodilation of coronary arterioles by 36 +/- 6%. Administration of N(G)-monomethyl-L-arginine (L-NMMA, 3 micromol.kg(-1).min(-1) intracoronary), indomethacin (10 mg/kg iv), and K(+) (60 mM, epicardial suffusion) to prevent the actions of nitric oxide, prostaglandins, and hyperpolarizing factors, respectively, partially inhibited dilation during ischemia (36 +/- 6 vs. 15 +/- 4%; P < 0.05). The residual vasodilation during ischemia after antagonist administration was inhibited by tin mesoporphyrin IX (SnMP, 10 mg/kg iv), which is an inhibitor of HO (15 +/- 4 vs. 7 +/- 2%; P < 0.05 vs. before SnMP). The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10(-5) M, epicardial suffusion) also inhibited vasodilation during ischemia in the presence of L-NMMA with indomethacin and KCl. Moreover, administration of heme-L-arginate, which is a substrate for HO, produced dilation after ischemia but not after control conditions. We conclude that during myocardial ischemia, HO-2 activation can produce cGMP-mediated vasodilation presumably via the production of CO. This vasodilatory pathway appears to play a backup role and is activated only when other mechanisms of vasodilation during ischemia are exhausted.
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PMID:In vivo role of heme oxygenase in ischemic coronary vasodilation. 1514 58

The present studies compared the effects of CO-releasing molecule (CORM-1), authentic CO, and nonadrenergic noncholinergic (NANC) nerve stimulation in the internal anal sphincter (IAS). Functional in vitro experiments and Western blot studies were conducted in rat IAS smooth muscle. We examined the effects of CORM-1 (50-600 microM) and authentic CO (5-100 microM) and NANC nerve stimulation by electrical field stimulation (EFS; 0.5-20 Hz, 0.5-ms pulse, 12 V, 4-s train). The experiments were repeated after preincubation of the tissues with the neurotoxin TTX, the guanylate cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), the selective heme oxygenase (HO) inhibitor tin protoporphyrin IX (SnPP-IX), the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NNA), and SnPP-IX + L-NNA. We also investigated the effects of the HO substrate hematin (100 microM). CORM-1, as well as CO, produced concentration-dependent IAS relaxation, whereas hematin had no effect. TTX abolished and L-NNA significantly blocked IAS relaxation by EFS without any effect on CORM-1 and CO. ODQ blocked IAS relaxation by CORM-1, authentic CO, and EFS. SnPP-IX had no significant effect on IAS relaxation by CORM-1, CO, or EFS. The presence of neuronal nitric oxide synthase, HO-1, and HO-2 in IAS smooth muscle was confirmed by Western blot studies. CORM-1 and CO, as well as NANC nerve stimulation, produced IAS relaxation via guanylate cyclase/cGMP-dependent protein kinase activation. The advent of CORM-1 with potent effects in the IAS has significant implications in anorectal motility disorders with regard to pathophysiology and therapeutic potentials.
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PMID:Mechanism of internal anal sphincter relaxation by CORM-1, authentic CO, and NANC nerve stimulation. 1533 53

Carbon monoxide (CO), an activator of soluble guanylate cyclase (SGC) and generated enzymatically by heme oxygenases (HO), is considered to function as an intra- and intercellular neuromodulator or neurotransmitter in the central and peripheral nervous systems. HO-2 is the constitutive isoform of HO and is more prevalent in nervous tissues than in the other peripheral tissues. Because previous studies have demonstrated different distributions of HO-2 in the retina depending on the species of animals, the aim of this study was to identify which cell types of the monkey retina express HO-2. The expression of HO-2 protein was examined in monkey retina by Western blot analysis. Immunoblottings from monkey homogenates revealed a single clear protein band with a molecular mass of 36 kDa that is corresponding to rat HO-2. Immunoreactivity of HO-2 was found in the perikarya of ganglion cells. Density of immunoreactive ganglion cells was higher in the central area of retina than in the peripheral retina, and somata of larger ganglion cells were stained more densely than smaller ones. In electron microscopy, immunoreactivity of HO-2 was localized on the membrane of the endoplasmic reticulum and the nuclear outer membrane of the ganglion cells. By contrast, inner plexiform layer, inner nuclear layer and outer nuclear layer were devoid of HO-2 immunoreactivity. cGMP were strongly localized in all of ganglion cells. Some cells contributed to the relatively faint cGMP staining were seen in the inner nuclear layer. In combination of HO-2 and cGMP immunocytochemistry, the overlap of co-localization of HO-2 and cGMP would suggest that HO-2 in the ganglion cells would serve as a source for CO generation and CO could serve as a gaseous signaling molecule modulator of neural activity in the retina of monkey.
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PMID:Cellular and subcellular localization of heme oxygenase-2 in monkey retina. 1552 May 26


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