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Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension.
Nozik-Grayck E, Woods C, Taylor JM, Benninger RK, Johnson RD, Villegas LR, Stenmark KR, Harrison DG, Majka SM, Irwin D, Farrow KN
(2014) Am J Physiol Lung Cell Mol Physiol 307: L868-76
MeSH Terms: Animals, Blood Pressure, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 5, Estrogen Antagonists, GTP Cyclohydrolase, Guanylate Cyclase, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Hypoxia, Lung, Mice, Mice, Knockout, Nitric Oxide Synthase Type III, Pulmonary Artery, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Soluble Guanylyl Cyclase, Superoxide Dismutase, Tamoxifen
Show Abstract · Added March 31, 2015
Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SOD(loxp/loxp) × Tg(cre/SMMHC) mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function.
Copyright © 2014 the American Physiological Society.
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20 MeSH Terms
Nitric oxide modulates bacterial biofilm formation through a multicomponent cyclic-di-GMP signaling network.
Plate L, Marletta MA
(2012) Mol Cell 46: 449-60
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Amino Acid Sequence, Bacterial Proteins, Biofilms, Cyclic GMP, Gammaproteobacteria, Guanylate Cyclase, Histidine Kinase, Models, Biological, Molecular Sequence Data, Nitric Oxide, Phosphorylation, Protein Kinases, Protein Structure, Tertiary, Receptors, Cytoplasmic and Nuclear, Second Messenger Systems, Sequence Homology, Amino Acid, Shewanella, Signal Transduction, Soluble Guanylyl Cyclase
Show Abstract · Added March 3, 2020
Nitric oxide (NO) signaling in vertebrates is well characterized and involves the heme-nitric oxide/oxygen-binding (H-NOX) domain of soluble guanylate cyclase as a selective NO sensor. In contrast, little is known about the biological role or signaling output of bacterial H-NOX proteins. Here, we describe a molecular pathway for H-NOX signaling in Shewanella oneidensis. NO stimulates biofilm formation by controlling the levels of the bacterial secondary messenger cyclic diguanosine monophosphate (c-di-GMP). Phosphotransfer profiling was used to map the connectivity of a multicomponent signaling network that involves integration from two histidine kinases and branching to three response regulators. A feed-forward loop between response regulators with phosphodiesterase domains and phosphorylation-mediated activation intricately regulated c-di-GMP levels. Phenotypic characterization established a link between NO signaling and biofilm formation. Cellular adhesion may provide a protection mechanism for bacteria against reactive and damaging NO. These results are broadly applicable to H-NOX-mediated NO signaling in bacteria.
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Receptor-type guanylate cyclase is required for carbon dioxide sensation by Caenorhabditis elegans.
Hallem EA, Spencer WC, McWhirter RD, Zeller G, Henz SR, Rätsch G, Miller DM, Horvitz HR, Sternberg PW, Ringstad N
(2011) Proc Natl Acad Sci U S A 108: 254-9
MeSH Terms: Animals, Base Sequence, Biological Evolution, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Carbon Dioxide, Chemotaxis, Cluster Analysis, DNA Primers, Gene Components, Guanylate Cyclase, Ion Channels, Microscopy, Confocal, Molecular Sequence Data, Neurons, Phylogeny, Receptors, Guanylate Cyclase-Coupled, Sequence Analysis, DNA, Smell, Transgenes
Show Abstract · Added February 21, 2014
CO(2) is both a critical regulator of animal physiology and an important sensory cue for many animals for host detection, food location, and mate finding. The free-living soil nematode Caenorhabditis elegans shows CO(2) avoidance behavior, which requires a pair of ciliated sensory neurons, the BAG neurons. Using in vivo calcium imaging, we show that CO(2) specifically activates the BAG neurons and that the CO(2)-sensing function of BAG neurons requires TAX-2/TAX-4 cyclic nucleotide-gated ion channels and the receptor-type guanylate cyclase GCY-9. Our results delineate a molecular pathway for CO(2) sensing and suggest that activation of a receptor-type guanylate cyclase is an evolutionarily conserved mechanism by which animals detect environmental CO(2).
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20 MeSH Terms
Nitric oxide mediates tightening of the endothelial barrier by ascorbic acid.
May JM, Qu ZC
(2011) Biochem Biophys Res Commun 404: 701-5
MeSH Terms: Ascorbic Acid, Capillary Permeability, Cell Line, Endothelium, Vascular, Guanylate Cyclase, Humans, Nitric Oxide, Nitric Oxide Synthase Type III, Vitamins
Show Abstract · Added December 5, 2013
Vitamin C, or ascorbic acid, decreases paracellular endothelial permeability in a process that requires rearrangement of the actin cytoskeleton. To define the proximal mechanism of this effect, we tested whether it might involve enhanced generation and/or sparing of nitric oxide (NO) by the vitamin. EA.hy926 endothelial cells cultured on semi-porous filter supports showed decreased endothelial barrier permeability to radiolabeled inulin in response to exogenous NO provided by the NO donor spermine NONOATE, as well as to activation of the downstream NO pathway by 8-bromo-cyclic GMP, a cell-penetrant cyclic GMP analog. Inhibition of endothelial nitric oxide synthase (eNOS) with N(ω)-nitro-l-arginine methyl ester increased endothelial permeability, indicating a role constitutive NO generation by eNOS in maintaining the permeability barrier. Inhibition of guanylate cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one also increased endothelial permeability and blocked barrier tightening by spermine NONOATE. Loading cells with what are likely physiologic concentrations of ascorbate decreased endothelial permeability. This effect was blocked by inhibition of either eNOS or guanylate cyclase, suggesting that it involved generation of NO by eNOS and subsequent NO-dependent activation of guanylate cyclase. These results show that endothelial permeability barrier function depends on constitutive generation of NO and that ascorbate-dependent tightening of this barrier involves maintaining NO through the eNOS/guanylate cyclase pathway.
Copyright © 2010 Elsevier Inc. All rights reserved.
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9 MeSH Terms
A soluble guanylate cyclase-dependent mechanism is involved in the regulation of net hepatic glucose uptake by nitric oxide in vivo.
An Z, Winnick JJ, Farmer B, Neal D, Lautz M, Irimia JM, Roach PJ, Cherrington AD
(2010) Diabetes 59: 2999-3007
MeSH Terms: Animals, Blood Glucose, Dogs, Female, Glucagon, Glucose, Guanylate Cyclase, Hematocrit, Hepatic Veins, Homeostasis, Insulin, Liver, Male, Nitric Oxide, Somatostatin
Show Abstract · Added January 20, 2015
OBJECTIVE - We previously showed that elevating hepatic nitric oxide (NO) levels reduced net hepatic glucose uptake (NHGU) in the presence of portal glucose delivery, hyperglycemia, and hyperinsulinemia. The aim of the present study was to determine the role of a downstream signal, soluble guanylate cyclase (sGC), in the regulation of NHGU by NO.
RESEARCH DESIGN AND METHODS - Studies were performed on 42-h-fasted conscious dogs fitted with vascular catheters. At 0 min, somatostatin was given peripherally along with 4× basal insulin and basal glucagon intraportally. Glucose was delivered at a variable rate via a leg vein to double the blood glucose level and hepatic glucose load throughout the study. From 90 to 270 min, an intraportal infusion of the sGC inhibitor 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) was given in -sGC (n = 10) and -sGC/+NO (n = 6), whereas saline was given in saline infusion (SAL) (n = 10). The -sGC/+NO group also received intraportal SIN-1 (NO donor) to elevate hepatic NO from 180 to 270 min.
RESULTS - In the presence of 4× basal insulin, basal glucagon, and hyperglycemia (2× basal ), inhibition of sGC in the liver enhanced NHGU (mg/kg/min; 210-270 min) by ∼55% (2.9 ± 0.2 in SAL vs. 4.6 ± 0.5 in -sGC). Further elevating hepatic NO failed to reduce NHGU (4.5 ± 0.7 in -sGC/+NO). Net hepatic carbon retention (i.e., glycogen synthesis; mg glucose equivalents/kg/min) increased to 3.8 ± 0.2 in -sGC and 3.8 ± 0.4 in -sGC/+NO vs. 2.4 ± 0.2 in SAL (P < 0.05).
CONCLUSIONS - NO regulates liver glucose uptake through a sGC-dependent pathway. The latter could be a target for pharmacologic intervention to increase meal-associated hepatic glucose uptake in individuals with type 2 diabetes.
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15 MeSH Terms
Opposing regulation of human alveolar type II cell differentiation by nitric oxide and hyperoxia.
Johnston LC, Gonzales LW, Lightfoot RT, Guttentag SH, Ischiropoulos H
(2010) Pediatr Res 67: 521-5
MeSH Terms: Alveolar Epithelial Cells, Biomarkers, Cell Differentiation, Cell Hypoxia, Cells, Cultured, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 5, Gene Expression Regulation, Gestational Age, Guanylate Cyclase, Humans, Nitric Oxide, Nuclear Proteins, Oxygen, Pulmonary Surfactant-Associated Protein B, Pulmonary Surfactant-Associated Protein C, RNA, Messenger, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Soluble Guanylyl Cyclase, Thyroid Nuclear Factor 1, Time Factors, Transcription Factors
Show Abstract · Added January 20, 2015
Clinical trials demonstrated decreasing rates of bronchopulmonary dysplasia in preterm infants with hypoxic respiratory failure treated with inhaled nitric oxide (iNO). However, the molecular and biochemical effects of iNO on developing human fetal lungs remain vastly unknown. By using a well-characterized model of human fetal alveolar type II cells, we assessed the effects of iNO and hyperoxia, independently and concurrently, on NO-cGMP signaling pathway and differentiation. Exposure to iNO increased cGMP levels by 40-fold after 3 d and by 8-fold after 5 d despite constant expression of phosphodiesterase-5 (PDE5). The levels of cGMP declined significantly on exposure to iNO and hyperoxia at 3 and 5 d, although expression of soluble guanylyl cyclase (sGC) was sustained. Surfactant proteins B and C (SP-B, SP-C) and thyroid transcription factor (TTF)-1 mRNA levels increased in cells exposed to iNO in normoxia but not on exposure to iNO plus hyperoxia. Collectively, these data indicate an increase in type II cell markers when undifferentiated lung epithelial cells are exposed to iNO in room air. However, hyperoxia overrides these potentially beneficial effects of iNO despite sustained expression of sGC.
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23 MeSH Terms
A gain-of-function screen in zebrafish identifies a guanylate cyclase with a role in neuronal degeneration.
Maddison LA, Lu J, Victoroff T, Scott E, Baier H, Chen W
(2009) Mol Genet Genomics 281: 551-63
MeSH Terms: Animals, Animals, Genetically Modified, Cyclic GMP, Female, Genetic Vectors, Guanylate Cyclase, Hybridization, Genetic, Male, Models, Neurological, Moloney murine leukemia virus, Mutagenesis, Insertional, Nerve Degeneration, Transcriptional Activation, Zebrafish
Show Abstract · Added April 24, 2014
Manipulation of gene expression is one of the most informative ways to study gene function. Genetic screens have been an informative method to identify genes involved in developmental processes. In the zebrafish, loss-of-function screens have been the primary approach for these studies. We sought to complement loss-of-function screens using an unbiased approach to overexpress genes with a Gal4-UAS based system, similar to the gain-of-function screens in Drosophila. Using MMLV as a mutagenic vector, a cassette containing a UAS promoter was readily inserted in the genome, often at the 5' end of genes, allowing Gal4-dependent overexpression. We confirmed that genes downstream of the viral insertions were overexpressed in a Gal4-VP16 dependent manner. We further demonstrate that misexpression of one such downstream gene gucy2F, a membrane-bound guanylate cyclase, throughout the nervous system results in multiple defects including a loss of forebrain neurons. This suggests proper control of cGMP production is important in neuronal survival. From this study, we propose that this gain-of-function approach can be applied to large-scale genetic screens in a vertebrate model organism and may reveal previously unknown gene function.
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14 MeSH Terms
Amygdala gene expression correlates of social behavior in monkeys experiencing maternal separation.
Sabatini MJ, Ebert P, Lewis DA, Levitt P, Cameron JL, Mirnics K
(2007) J Neurosci 27: 3295-304
MeSH Terms: Age Factors, Amygdala, Animals, Animals, Newborn, Female, Gene Expression Regulation, Developmental, Guanylate Cyclase, Macaca mulatta, Maternal Behavior, Maternal Deprivation, Receptors, Cytoplasmic and Nuclear, Social Behavior, Soluble Guanylyl Cyclase
Show Abstract · Added May 19, 2014
Children exposed to early parental loss from death or separation carry a greater risk for developing future psychiatric illnesses, such as major depression and anxiety. Monkeys experiencing maternal separation at 1 week of age show fewer social behaviors and an increase in self-comforting behaviors (e.g., thumb sucking) over development, whereas in contrast, monkeys experiencing maternal separation at 1 month of age show increased seeking of social comfort later in life. We sought to identify neural systems that may underlie these stress-induced behavioral changes by examining changes in mRNA content in amygdala tissue collected from 1 week separated, 1 month separated, and maternally reared infants at 3 months of age. mRNA from the right medial temporal lobe, primarily the amygdala, was analyzed using Affymetrix U133A 2.0 arrays. One gene, guanylate cyclase 1 alpha 3 (GUCY1A3), showed differential expression between the 1 week and maternally reared groups and the 1 week and 1 month groups; these changes were confirmed by in situ hybridization. The expression of this gene was positively correlated with acute social-comforting behavior (r = 0.923; p = 0.001) and longer-term close social behavior (r = 0.708; p = 0.015) and negatively correlated with self-comforting behaviors (r = -0.88; p < 0.001). Additional in situ hybridization studies of GUCY1A3 in normal monkeys showed that this gene is expressed at adult levels by 1 week of age and that its expression is greater in the amygdala than all other brain areas examined. We conclude that GUCY1A3 may contribute to the altered behavioral phenotypes that are differentially displayed depending on the age at which macaque infants experience an early-life stress.
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13 MeSH Terms
cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism.
Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA
(2005) Circ Res 96: 100-9
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Adenoviridae, Adrenergic beta-Agonists, Animals, Carbolines, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 5, Fluorescence Resonance Energy Transfer, Genetic Vectors, Guanylate Cyclase, Isoproterenol, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Phosphodiesterase Inhibitors, Piperazines, Purines, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta, Receptors, Cytoplasmic and Nuclear, Recombinant Fusion Proteins, Second Messenger Systems, Sildenafil Citrate, Soluble Guanylyl Cyclase, Sulfones, Tadalafil
Show Abstract · Added March 4, 2015
Beta-adrenergic agonists stimulate cardiac contractility and simultaneously blunt this response by coactivating NO synthase (NOS3) to enhance cGMP synthesis and activate protein kinase G (PKG-1). cGMP is also catabolically regulated by phosphodiesterase 5A (PDE5A). PDE5A inhibition by sildenafil (Viagra) increases cGMP and is used widely to treat erectile dysfunction; however, its role in the heart and its interaction with beta-adrenergic and NOS3/cGMP stimulation is largely unknown. In nontransgenic (control) murine in vivo hearts and isolated myocytes, PDE5A inhibition (sildenafil) minimally altered rest function. However, when the hearts or isolated myocytes were stimulated with isoproterenol, PDE5A inhibition was associated with a suppression of contractility that was coupled to elevated cGMP and increased PKG-1 activity. In contrast, NOS3-null hearts or controls with NOS inhibited by N(G)-nitro-L-arginine methyl ester, or soluble guanylate cyclase (sGC) inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, showed no effect of PDE5A inhibition on beta-stimulated contractility or PKG-1 activation. This lack of response was not attributable to altered PDE5A gene or protein expression or in vitro PDE5A activity, but rather to an absence of sGC-generated cGMP specifically targeted to PDE5A catabolism and to a loss of PDE5A localization to z-bands. Re-expression of active NOS3 in NOS3-null hearts by adenoviral gene transfer restored PDE5A z-band localization and the antiadrenergic efficacy of PDE5A inhibition. These data support a novel regulatory role of PDE5A in hearts under adrenergic stimulation and highlight specific coupling of PDE5A catabolic regulation with NOS3-derived cGMP attributable to protein subcellular localization and targeted synthetic/catabolic coupling.
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34 MeSH Terms
Adenosine receptor, protein kinase G, and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation.
Zhu CB, Hewlett WA, Feoktistov I, Biaggioni I, Blakely RD
(2004) Mol Pharmacol 65: 1462-74
MeSH Terms: Adenosine-5'-(N-ethylcarboxamide), Animals, Biological Transport, CHO Cells, Calcium, Carrier Proteins, Cells, Cultured, Cricetinae, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Female, Guanylate Cyclase, Membrane Glycoproteins, Membrane Transport Proteins, Mitogen-Activated Protein Kinases, Nerve Tissue Proteins, Phosphodiesterase Inhibitors, Piperazines, Purines, Rats, Receptors, Purinergic P1, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sildenafil Citrate, Sulfones, Type C Phospholipases, Up-Regulation, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added December 10, 2013
Serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) are critical determinants of synaptic 5-HT inactivation and the targets for multiple drugs used to treat psychiatric disorders. In support of prior studies, we found that short-term (5-30 min) application of the adenosine receptor (AR) agonist 5'-N-ethylcarboxamidoadenosine (NECA) induces an increase in 5-HT uptake Vmax in rat basophilic leukemia 2H3 cells that is enhanced by pretreatment with the cGMP phosphodiesterase inhibitor sildenafil. NECA stimulation is blocked by the A3 AR antagonist 3-ethyl-5-benzyl-2-methyl-phenylethynyl-6-phenyl-1,4(+/-)dihydropyridine-3,5-dicarboxylate (MRS1191), by the phospholipase C inhibitor 1-(6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl] amino]hexyl)-1H-pyrrole-2,5-dione (U73122), by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, and by the guanyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Hydroxylamine, a nitric-oxide donor, and 8-bromo-cGMP, a membrane-permeant analog of cGMP, mimic the effects of NECA on 5-HT uptake, whereas the protein kinase G (PKG) inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8) blocks NECA, hydroxylamine, and 8-bromo-cGMP effects. NECA stimulation activates p38 mitogen-activated protein kinase (MAPK), whereas p38 MAPK inhibitors block NECA stimulation of SERT activity, as does the protein phosphatase 2A (PP2A) inhibitor calyculin A. 5-HT-displaceable [125I]3beta-(4-iodophenyl)-tropane-2beta-carboxylic acid methylester tartrate (RTI-55) whole-cell binding is increased by NECA or sildenafil, and both surface binding and cell surface SERT protein are elevated after NECA or sildenafil stimulation of AR/SERT-cotransfected Chinese hamster ovary cells. Whereas p38 MAPK inhibition blocks NECA stimulation of 5-HT activity, it fails to blunt stimulation of SERT surface density. Moreover, inactivation of existing surface SERTs fails to eliminate NECA stimulation of SERT. Together, these results reveal two PKG-dependent pathways supporting rapid SERT regulation by A3 ARs, one leading to enhanced SERT surface trafficking, and a separate, p38 MAPK-dependent process augmenting SERT intrinsic activity.
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28 MeSH Terms