Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Heme oxygenase-1 (HO-1) has been implicated in antioxidant and anti-inflammatory actions. To characterize the role of HO-1 in the vascular inflammatory response, we examined the effect of HO-1 on the expression of inducible nitric oxide synthase (iNOS) induced by interleukin-1beta (IL-1beta) in rat vascular smooth muscle cells (VSMCs). Western blot analysis demonstrated that IL-1beta-induced iNOS expression was significantly reduced by hemin cotreatment or adenovirus-mediated HO-1 gene transfer. Scavenging carbon monoxide (CO), one of the by-products of heme degradation by HO-1, significantly attenuated HO-1-mediated suppression of iNOS gene induction as revealed by Northern blot analysis. Exposure of cells to CO or a CO donor, the tricarbonyldichlororuthenium(II) dimer, also markedly inhibited IL-1beta-induced iNOS expression. Transient transfection experiments with a reporter gene construct carrying the rat iNOS gene promoter demonstrated that IL-1beta-induced promoter activity was substantially reduced by cotreatment with CO or a CO donor. Furthermore, the effects of CO on iNOS gene promoter activity and protein expression were diminished by cotreatment with the specific guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo-(4,3-a)quinoxalin-1-one. These data support the finding that HO-1 attenuates IL-1beta-induced iNOS gene expression in VSMCs. CO appears to mediate the suppressive effect of HO-1, at least in part, through downregulating transcriptional activation of the iNOS gene via a cGMP-dependent pathway.
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PMID:Heme oxygenase-1 attenuates interleukin-1beta-induced nitric oxide synthase expression in vascular smooth muscle cells. 1559 77

Enterocytes maintain fluid-electrolyte homeostasis by keeping a tight barrier and regulating ion channels. Carbon monoxide (CO), a product of heme degradation, modulates electrolyte transport in kidney and lung epithelium, but its role in regulating intestinal fluid-electrolyte homeostasis has not been studied. The major source of endogenous CO formation comes from the degradation of heme via heme oxygenase. We hypothesized that heme activates electrolyte transport in intestinal epithelial cells. Basolateral hemin treatment increased baseline Caco-2 cell short-circuit currents (I(sc)) twofold (control = 1.96 +/- 0.14 microA/cm(2) vs. hemin = 4.07 +/- 0.16 microA/cm(2), P < 0.01); apical hemin had no effect. Hemin-induced I(sc) was caused by Cl- secretion because it was inhibited in Cl- -free medium, with ouabain, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), or DIDS. Apical electrogenic Na+ channel inhibitor benzamil had no effect on hemin-induced I(sc). Hemin did not alter the ability of Caco-2 cells to respond maximally to forskolin, but a soluble guanylate cyclase inhibitor, [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) inhibited the effects of hemin. A CO-releasing molecule, tricarbonyldichlororuthenium II, induced active Cl- secretion that was also inhibited with ODQ. We conclude that hemin induces active Cl- secretion in Caco-2 cells via a cGMP-dependent pathway. These effects are probably the consequence of CO formation. Heme and CO may be important regulators of intestinal fluid-electrolyte homeostasis.
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PMID:Hemin induces active chloride secretion in Caco-2 cells. 1580

Soluble guanylate cyclase (sGC) is a nitric oxide (NO) sensing hemoprotein that has been found in eukaryotes from Drosophila to humans. Prokaryotic proteins with significant homology to the heme domain of sGC have recently been identified through genomic analysis. This family of heme proteins has been named the H-NOX domain, for Heme-Nitric oxide/OXygen binding domain. The key observation from initial studies in this family is that some members, those proteins from most eukaryotes and facultative aerobic prokaryotes, bind NO in a five-coordinate heme complex, but do not bind oxygen (O(2)), the same ligand binding characteristics as sGC. H-NOX family members from obligate aerobic prokaryotes bind O(2) and NO in six-coordinate complexes, similar to the globins and other O(2)-sensing heme proteins. The molecular factors that contribute to these differences in ligand specificity, within a family of sequence related proteins, are the subject of this review.
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PMID:Ligand specificity of H-NOX domains: from sGC to bacterial NO sensors. 1581 6

Thromboembolism--and its involvement with tissue infarction and ischemic necrosis--continues to be of major importance in the area of vascular biology that affects all areas of clinical medicine. Activated platelets and their aggregations are key initiators in the formation of the thrombus. Several mechanisms have been described to modulate thrombus formation in the circulation, such as prostacyclins and endothelium-derived relaxing factors (the most studied being nitric oxide). Similar to nitrous oxide (NO), carbon monoxide (CO) can modulate guanylate cyclase and has been associated with anti-inflammatory and anti-apoptotic activities. Heme oxygenase (HO), in addition to being the rate-limiting enzyme of CO generation, degrades heme, which is a pro-oxidant/pro-inflammatory and generates the antioxidant molecules biliverdin and bilirubin. HO-2 is generally considered to be enriched in the brain. Here, by studying mouse platelets, we showed that it is highly present in wildtype (WT) animals and not detectable in HO-2 knockout mice. A similar finding was observed in female rats. We also investigated whether modification of estrogen levels (naturally occurring, with age, or surgically) and estrogen replacement would affect intraplatelet HO levels. Under these chronic conditions, HO-1 was barely detectable, while HO-2 was consistently stably expressed at high levels. Further investigation into the functional properties of HO itself, heme degradation, and heme bioactive metabolites remains to be conducted to determine the role of HO on platelet dynamics and on microvasculature.
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PMID:Characterization of heme oxygenase in adult rodent platelets. 1618 Nov 9

Nitric oxide (NO) mediates cell signaling at low (nanomolar) concentrations, but can be cytotoxic at higher concentrations. Heme oxygenase-1 (HO-1), implicated in a role in NO resistance, might confer its protective effect through the direct products biliverdin and CO or the secondary product bilirubin. We have therefore tested whether biliverdin, bilirubin, or CO can provide resistance to NO toxicity. HeLa cells treated with bilirubin or biliverdin (up to 25 microM) had unchanged survival of an NO challenge (1 mM spermine-NONOate or 2 mM DEA-NO), although they displayed increased resistance to H2O2 (350 microM). In contrast, prior exposure to CO (up to 100 ppm) increased NO resistance. An interval between CO exposure and NO resistance was required for the increased NO resistance. Because the CO-activated NO resistance was also blocked by the transcription inhibitor actinomycin D, inducible gene expression seems critical for the cytoprotection elicited by CO. Experiments in the presence of HO and guanylate cyclase inhibitors indicated that HO activity and cGMP signaling are not essential for the CO-protective effect. Last, inhibition of p38 MAPK activation fully blocked the CO-protective effect, indicating the involvement of this signaling pathway(s) in the CO response.
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PMID:Carbon monoxide mediates protection against nitric oxide toxicity in HeLa cells. 1619 34

Density functional theory calculations (PW91/STO-TZP, including basis-set superposition error corrections) have been used to evaluate hydrogen bond energies of five- and six-coordinate heme-NO complexes with phenol and imidazole, chosen as models for distal pocket tyrosine and histidine residues. The calculated interaction energies are approximately 2 kcal/mol for phenol and 3-4 kcal/mol for imidazole, which are 2-4 times smaller than the energies calculated for heme-O(2) complexes hydrogen-bonding with a distal histidine. Interestingly, the hydrogen bond energies are found to be very similar for five- and six-coordinate heme-NO complexes, which may be viewed as contrary to the interpretation of a recent observation on a bacterial H-NOX (Heme-Nitric oxide/OXygen-binding) protein with sequence homology to mammalian-soluble guanylate cyclase.
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PMID:Toward modeling H-NOX domains: a DFT study of heme-NO complexes as hydrogen bond acceptors. 1624 Nov 29

The heme cofactor in soluble guanylate cyclase (sGC) is a selective receptor for NO, an important signaling molecule in eukaryotes. The sGC heme domain has been localized to the N-terminal 194 amino acids of the beta1 subunit of sGC and is a member of a family of conserved hemoproteins, called the H-NOX family (Heme-Nitric Oxide and/or OXygen-binding domain). Three new members of this family have now been cloned and characterized, two proteins from Legionella pneumophila (L1 H-NOX and L2 H-NOX) and one from Nostoc punctiforme (Np H-NOX). Like sGC, L1 H-NOX forms a 5-coordinate Fe(II)-NO complex. However, both L2 H-NOX and Np H-NOX form temperature-dependent mixtures of 5- and 6-coordinate Fe(II)-NO complexes; at low temperature, they are primarily 6-coordinate, and at high temperature, the equilibrium is shifted toward a 5-coordinate geometry. This equilibrium is fully reversible with temperature in the absence of free NO. This process is analyzed in terms of a thermally labile proximal Fe(II)-His bond and suggests that in both the 5- and 6-coordinate Fe(II)-NO complexes of L2 H-NOX and Np H-NOX, NO is bound in the distal heme pocket of the H-NOX fold. NO dissociation kinetics for L1 H-NOX and L2 H-NOX have been determined and support a model in which NO dissociates from the distal side of the heme in both 5- and 6-coordinate complexes.
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PMID:Nitric oxide binding to prokaryotic homologs of the soluble guanylate cyclase beta1 H-NOX domain. 1672 1

Heme oxygenases (HO-1 and HO-2) catalyze the conversion of heme to carbon monoxide (CO), iron, and biliverdin. CO causes vasorelaxation via stimulation of soluble guanylate cyclase (sGC) and/or activation of calcium-activated potassium channels. Because nitric oxide (NO) exerts effects via the same pathways, we tested the interaction between CO and NO on rat afferent arterioles (AAs) using the blood-perfused juxtamedullary nephron preparation. AAs were superfused with either tricarbonyldichlororuthenium (II) dimer, known as CO releasing molecule (CORM-2), 10 micromol/l CO solution, or 15 micromol/l chromium mesoporphyrin (CrMP, HO inhibitor). AAs were also superfused with 1 mmol/l N(omega)-nitro-L-arginine (L-NNA) to inhibit NO synthase (NOS) or 10 micromol/l 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one to inhibit sGC, and then CrMP was superfused during NOS inhibition or sGC inhibition. Treatment with 150 and 300 micromol/l CORM-2 or with CO (10 micromol/l) significantly dilated AAs (22.0 +/- 0.9 and 22.8 +/- 0.9 vs. 18.3 +/- 0.9 microm, n = 5, P < 0.05; and 26.0 +/- 1.4 vs. 18.8 +/- 0.7 microm, n = 5, P < 0.05). In untreated vessels, HO inhibition did not alter AA diameter (17.5 +/- 0.7 vs. 17.2 +/- 0.6 microm, n = 7, P > 0.05); however, during inhibition of NO production, which constricted arterioles to 14.6 +/- 1.2 microm, n = 6, P < 0.05, concurrent HO inhibition led to further vasoconstriction (11.7 +/- 1.6 microm, n = 6, P < 0.05). CORM-2 attenuated the L-NNA-induced vasoconstriction. Inhibition of sGC caused significant constriction (15.7 +/- 0.4 vs. 18.8 +/- 0.4 microm, n = 6, P < 0.05). HO inhibition during sGC inhibition did not cause further change in AAs (15.5 +/- 0.7 microm, n = 6). We conclude that endogenously produced CO does not exert a perceptible influence on AA diameter in the presence of intact NO system; however, when NO production is inhibited, CO serves as an important renoprotective reserve mechanism to prevent excess afferent arteriolar constriction.
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PMID:Interaction between endogenously produced carbon monoxide and nitric oxide in regulation of renal afferent arterioles. 1684 15

Heme oxygenase (HO)-1, an inducible, low-molecular-weight stress protein, confers cellular and tissue protection in multiple models of injury and disease, including oxidative or inflammatory lung injury, ischemia/reperfusion (I/R) injuries, and vascular injury/disease. The tissue protection provided by HO-1 potentially relates to the endogenous production of the end products of its enzymatic activity: namely, biliverdin (BV)/bilirubin (BR), carbon monoxide (CO), and iron. Of these, CO and BV/BR show promise as possible therapeutic agents when applied exogenously in models of lung or vascular injury. CO activates intracellular signaling pathways that involve soluble guanylate cyclase and/or p38 mitogen-activated protein kinase. Although toxic at elevated concentrations, low concentrations of CO can confer antiinflammatory, antiapoptotic, antiproliferative, and vasodilatory effects. BV and BR are natural antioxidants that can provide protection against oxidative stress in cell culture and in plasma. Application of BV or BR protects against I/R injury in several organ models. Recent evidence has also demonstrated antiinflammatory and antiproliferative properties of these pigments. To date, evidence has accumulated for salutary effects of CO, BV, and/or BR in lung/vascular injury models, as well as in models of transplant-associated I/R injury. Thus, the exogenous application of HO end products may provide an alternative to pharmacologic or gene therapy approaches to harness the therapeutic potential of HO-1.
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PMID:Carbon monoxide and bilirubin: potential therapies for pulmonary/vascular injury and disease. 1698 May 50


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