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Role of constitutive nitric oxide synthase S-nitrosylation in Helicobacter pylori-induced gastric mucosal cell apoptosis: effect of ghrelin

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Abstract

Infection with H. pylori is a primary factor in the etiology of gastric disease, and the excessive NO generation and a massive rise in apoptosis are well recognized features that characterize the mucosal inflammatory responses to the bacterium and its lipopolysaccharide (LPS). Here, we report that H. pylori LPS-induced enhancement in gastric mucosal cell apoptosis and NO generation was associated with the suppression in constitutive nitric oxide synthase (cNOS) activity and a marked up-regulation in the activity of inducible nitric oxide synthase (iNOS). Further, we demonstrate that the detrimental effect of the LPS on cNOS was manifested in the enzyme protein S-nitrosylation, that was susceptible to suppression by iNOS inhibitor, 1400W. Moreover, we show that the countering effect of peptide hormone, ghrelin, on the LPS-induced changes in apoptosis and cNOS activity was reflected in the loss in cNOS S-nitrosylation and the increase in the enzyme phosphorylation. These findings demonstrate that the disturbances in gastric mucosal NO generation system caused by H. pylori result from the iNOS-derived NO suppression of cNOS activation through S-nitrosylation. We also report that ghrelin protection against H. pylori-induced gastric mucosal proapoptotic events involves cNOS activation manifested by the increase in enzyme protein phosphorylation and a decrease in its S-nitrosylation.

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References

  • Chanvorachote P, Nimmannit U, Wang L et al (2005) Nitric oxide negatively regulates Fas CD95-induced apoptosis through inhibition of ubiquitin-proteosome-mediated degradation of FLICE inhibitory protein. J Biol Chem 280:42044–42050

    Article  CAS  PubMed  Google Scholar 

  • Colasanti M, Suzuki H (2000) The dual personality of NO. Trends Pharmacol Sci 21:249–252

    Article  CAS  PubMed  Google Scholar 

  • Cuzzocrea S, Salvemini D (2007) Molecular mechanisms involved in the reciprocal regulation of cyclooxygenase and nitric oxide synthase enzymes. Kidney Int 71:290–297

    Article  CAS  PubMed  Google Scholar 

  • de Boer WA (2000) Topics in Helicobacter pylori infection: focus on a ‘search-and-treat’ strategy for ulcer disease. Scand J Gastroenterol 35(suppl 32):4–9

    Google Scholar 

  • Erwin PA, Lin AJ, Golan E et al (2005) Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem 280:19888–19894

    Article  CAS  PubMed  Google Scholar 

  • Erwin PA, Mitchell DA, Sartoretto J et al (2006) Subcellular targeting and differential S-nitrosylation of endothelial nitric-oxide synthase. J Biol Chem 281:151–157

    Article  CAS  PubMed  Google Scholar 

  • Forrester MT, Forrester MW, Stamler JS (2007) Assessment and application of the biotin switch technique for examining protein S-nitrosylation under conditions of pharmacologically induced oxidative stress. J Biol Chem 282:13977–13983

    Article  CAS  PubMed  Google Scholar 

  • Fu S, Ramanujan KS, Wong A, Fantry GT et al (1999) Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase-2 in Helicobacter pylori gastritis. Gastroenterology 116:1319–1329

    Article  CAS  PubMed  Google Scholar 

  • Fulton D, Gratton JP, Sessa WC (2001) Post-translational control of endothelial NO synthase: why isn’t calcium/calmodulin enough? J Pharmacol Exp Ther 299:818–824

    CAS  PubMed  Google Scholar 

  • Gonzalez E, Kou R, Lin AJ et al (2002) Subcellular targeting and antagonist -induced site-specific phosphorylation of endothelial nitric-oxide synthase. J Biol Chem 277:39554–39560

    Article  CAS  PubMed  Google Scholar 

  • Gupta RA, Polk DB, Krishna U et al (2001) Activation of peroxisome proliferator-activated receptor γ suppresses nuclear factor κB-mediated apoptosis induced by Helicobacter pylori in gastric epithelial cells. J Biol Chem 276:31059–31066

    Article  CAS  PubMed  Google Scholar 

  • Gyires K (2005) Gastric mucosal protection: from prostaglandin to gene-therapy. Curr Med Chem 12:203–215

    CAS  PubMed  Google Scholar 

  • Haynes MP, Li L, Sinha D et al (2003) Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem 278:2118–2123

    Article  CAS  PubMed  Google Scholar 

  • Jaffrey SR, Erdjument-Bromage H, Ferris D et al (2001) Protein S-nitrosylation: a physiological signal for neuronal nitric acid. Nat Cell Biol 3:193–197

    Article  CAS  PubMed  Google Scholar 

  • Kim YM, Talanian RV, Billiar TR (1997) Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J Biol Chem 272:31138–31148

    Article  CAS  PubMed  Google Scholar 

  • Kojima M, Hosoda H, Date Y et al (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660

    Article  CAS  PubMed  Google Scholar 

  • Korhonen R, Lahti A, Kankaanranta H, Moilanen E (2005) Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy 4:471–479

    Article  CAS  PubMed  Google Scholar 

  • Lelamali K, Wang W, Gengaro P et al (2001) Effects of nitric oxide and peroxynitrite on endotoxin-induced leukocyte adhesion to endothelium. J Cell Phys 188:337–342

    Article  CAS  Google Scholar 

  • Maa MC, Chang MY, Chen YJ et al (2008) Requirement of inducible nitric-oxide synthase in lipopolysaccharide-mediated Src induction and macrophage migration. J Biol Chem 283:31408–31416

    Article  CAS  PubMed  Google Scholar 

  • Mannick JB (2007) Regulation of apoptosis by protein S-nitrosylation. Amino Acids 32:523–526

    Article  CAS  PubMed  Google Scholar 

  • Osawa H, Nakazato M, Date Y et al (2005) Impaired production of gastric ghrelin in chronic gastritis associated with Helicobacter pylori. J Clin Endocirnol Metab 90:10–16

    Article  CAS  Google Scholar 

  • Piotrowski J (1998) Lipopolysaccharide a virulence factor of Helicobacter pylori. J Physiol Pharmacol 49:3–24

    CAS  PubMed  Google Scholar 

  • Piotrowski J, Piotrowski E, Skrodzka D et al (1997) Induction of acute gastritis and epithelial cell apoptosis by Helicobacter pylori lipopolysaccharide. Scand J Gastroenterol 32:203–211

    Article  CAS  PubMed  Google Scholar 

  • Sibilia V, Pagani F, Rindi G et al (2008) Central ghrelin gastroprotection involves nitric oxide/prostaglandin cross-talk. Br J Pharmacol 154:688–697

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2001) Blockade of p38 mitogen-activated protein kinase pathway inhibits inducible nitric oxide synthase and gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide by peroxisome proliferator-activated receptor γ activation. Inflammopharmacology 8:371–382

    Article  Google Scholar 

  • Slomiany BL, Slomiany A (2004) Platelet-activating factor mediates Helicobacter pylori lipopolysaccharide interference with gastric mucin synthesis. IUBMB Life 56:41–46

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2008) Leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways. Inflammopharmacology 16:76–82

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2009) Involvement of constitutive nitric oxide synthase in ghrelin-induced cytosolic phospholipase A2 activation in gastric mucosal cell protection against ethanol cytotoxicity. Inflammopharmacology 17:245–253

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2010) Ghrelin protection against lipopolysaccharide-induced gastric mucosal cell apoptosis involves constitutive nitric oxide synthase-mediated caspase-3 S-nitrosylation. Mediators Inflammation. doi:10.1155/2010/28046410.1155/2010/280464

  • Slomiany BL, Piotrowski J, Slomiany A (1999) Gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide: down-regulation of nitric oxide synthase-2 and caspase-3 by sulglycotide. Biochem Biophys Res Commun 261:15–20

    Article  CAS  PubMed  Google Scholar 

  • Sun J, Steenbergen C, Murphy E (2006) S-nitrosylation: NO-related redox signaling to protect against oxidative stress. Antioxid Redox Signal 8:1693–1705

    Article  CAS  PubMed  Google Scholar 

  • Vecchione C, Maffei A, Colella S et al (2002) Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway. Diabetes 51:168–173

    Article  CAS  PubMed  Google Scholar 

  • Wagner DA, Glogowski J, Skipper PL et al (1982) Analysis of nitrate, nitrite and [15N]nitrate in biological fluids. Anal Biochem 126:131–138

    Article  PubMed  Google Scholar 

  • Waseem T, Duxbury M, Ito H et al (2008) Exogenous ghrelin modulates release of proinflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery 143:334–342

    Article  PubMed  Google Scholar 

  • Xu X, Jhun BS, Ha CH et al (2008) Molecular mechanisms of ghrelin-mediated endothelial nitric-oxide synthase activation. Endocrinology 149:4183–4192

    Article  CAS  PubMed  Google Scholar 

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  1. Research Center, C875, New Jersey Dental School, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA

    B. L. Slomiany & A. Slomiany

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  1. B. L. Slomiany
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  2. A. Slomiany
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Correspondence to B. L. Slomiany.

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Slomiany, B.L., Slomiany, A. Role of constitutive nitric oxide synthase S-nitrosylation in Helicobacter pylori-induced gastric mucosal cell apoptosis: effect of ghrelin. Inflammopharmacol 18, 233–240 (2010). https://doi.org/10.1007/s10787-010-0051-7

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  • DOI: https://doi.org/10.1007/s10787-010-0051-7

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