Cytosolic phospholipase A2 S-nitrosylation in ghrelin protection against detrimental effect of ethanol cytotoxicity on gastric mucin synthesis ——Ghrelin in gastric mucosal protection
Bronislaw L. Slomiany, Amalia Slomiany
DOI: 10.4236/health.2010.29152   PDF   HTML     3,964 Downloads   7,058 Views   Citations


Ghrelin, a peptide hormone produced mainly in the stomach, has emerged recently as an important regulator of nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems, the products of which play direct cytoprotective function in the maintenance of gastric mucosal integrity. In this study, using gastric mucosal cells, we report on the role of ghrelin in countering the cytotoxic effect of ethanol on mucin synthesis. We show that the countering effect of ghrelin on mucin synthesis was associated with the increase in NO and PGE2 production, and characterized by a marked up-regulation in cytosolic phospholipase A2 (cPLA2) activity. The ghrelin-induced up-regulation in mucin synthesis, like that of cPLA2 activity, was subject to suppression by Src inhibitor, PP2 and ERK inhibitor, PD98059, as well as ascorbate. Moreover, the loss in countering effect of ghrelin on the ethanol cytotoxicity and mucin synthesis was attained with cNOS inhibitor, L-NAME as well as COX-1 inhibitor SC-560. The effect of L-NAME was reflected in the inhibition of ghrelin-induced mucosal cell capacity for NO production, cPLA2 S-nitrosylation and PGE2 generation, whereas COX-1 inhibitor caused only the inhibition in PGE2 generation. Our findings suggest that the activation of gastric mucosal cPLA2 through cNOS-induced S-nitrosylation plays an essential role in the countering effect of ghrelin on the disturbances in gastric mucin synthesis caused by ethanol cytotoxicity.

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Slomiany, B. and Slomiany, A. (2010) Cytosolic phospholipase A2 S-nitrosylation in ghrelin protection against detrimental effect of ethanol cytotoxicity on gastric mucin synthesis ——Ghrelin in gastric mucosal protection. Health, 2, 1033-1039. doi: 10.4236/health.2010.29152.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Guslandi, M. (1987) Effects of ethanol on the gastric mucosa. Digestive Diseases Sciences, 5, 21-32.
[2] Konturek, S.J., Brzozowski, T., Konturek, W. and Slomiany, B.L. (1993) Growth factors in gastric mucosal integrity, protection and healing of acute and chronic ulcerations. In: Domschke, W. and Konturek, S.J., Eds., The Stomach, Springer-Verlag, Berlin, 159-176.
[3] Slomiany, A., Morita, M., Sano, S., Piotrowski, J., Skro- dzka, D. and Slomiany, B.L. (1997) Effect of ethanol on mucus glycoprotein synthesis, translocation, transport, glycosylation and secretion. Alcoholism: Clinical and Experimental Research, 21, 417-423.
[4] Konturek, P.C., Brzozowski, T., Pajdo, R., Ptak, A., Ni- kiforuk, A., Pawlik, W.W. and Hahn, E.G. (2004) Ghrelin-A new gastroprotective factor in gastric mucosa. Journal of Physiology and Pharmacology, 55(2), 325- 336.
[5] Slomiany, B.L. and Slomiany, A. (2008) Src kinase- mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways in leptin protection of gastric mucosa against ethanol cytotoxicity. Journal of Physiology and Pharmacology, 59(2), 301-314.
[6] Slomiany, B.L. and Slomiany, A. (1993) Mucus and gastric mucosal protection. In: Domschke, W. and Konturek, S.J., Eds., The Stomach, Springer-Verlag, Berlin, 116- 143.
[7] Silen, W. (1987) Gastric mucosal defense and repair. In: Johnson, L.R., Ed., Physiology of the Gastrointestinal Tract, 2nd Edition. Raven Press, New York, 1055-1069.
[8] Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H. and Kangawa, K. (1999) Ghrelin is a growth-hormone- releasing acylated peptide from stomach. Nature, 402 (6762), 656-660.
[9] Sibilia, V., Pagani, F., Rindi, G., Lattauda, N., Rapetti, D., De Luca, V., Campanini, N., Bulgarelli, I., Locatelli, V., Guidobono, F. and Netti, C. (2008) Central ghrelin gastroprotection involves nitric oxide/prostaglandin cross-talk. British Journal of Pharmacology, 154(3), 688-697.
[10] Ceranowicz, P., Warzecha, Z., Dembinski, A., Sendur, R., Cieszkowski, J., Ceranowicz, D., Pawlik, W.W., Kuwahara, A., Kato, I. and Konturek, P.C. (2009) Treatment with ghrelin accelerates the healing of acetic acid-induced gastric and duodenal ulcers in rats. Journal of Physiology and Pharmacology, 60(1), 87-98.
[11] Whittle, B.J., Lopez-Belmonte, J. and Moncada, S. (1990) Regulation of gastric mucosal integrity by endogenous nitric oxide: Interactions with prostanoids and sensory neuropeptides in the rat. British Journal of Pharmacology, 99(3), 607-611.
[12] Peskar, B.M. (2001) Role of cyclooxygenase isoforms in gastric mucosal defense. Journal of Physiology (Paris) 95(1-6), 3-9.
[13] Price, K. and Hanson, P. (1998) Constitutive nitric oxide synthase in rat gastric mucosa: Subcellular distribution, relative activity and different carboxyl-terminal antigenicity of the neuronal form compared with cerebellum. Digestion, 59, 308-313.
[14] Kim, S.F., Huri, D.A. and Snyder, S.H. (2005) Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science, 310(5756), 1966-1970.
[15] Clancy, R., Varenika, B., Huang, W., Ballou, L., Attur, M., Amin, A.R. and Abramson, S.B. (2000) Nitric oxide synthase/COX cross-talk: Nitric oxide activates COX-1 but inhibits COX-2 derived prostaglandin production. Journal of Immunology, 165(3), 1582-1587.
[16] Marnett, L.J., Wright, T.L., Crews, B.C., Tannenbaum, S.R. and Morrow, J.D. (2000) Regulation of prostaglan- din biosynthesis by nitric oxide is revealed by target deletion of inducible nitric-oxide synthase. Journal of Biological Chemistry, 275(18), 13427-13430.
[17] Cuzzocrea, S. and Salvemini, D. (2007) Molecular me- chanisms involved in the reciprocal regulation of cyclo- oxygenase and nitric oxide synthase enzymes. Kidney International, 71(4), 290-297.
[18] Xu, L., Han, C., Lim, K. and Wu, T. (2008). Activation of cytosolic phospholipase A2 ?through nitric oxide-induced S-nitrosylation. Involvement of inducible nitric-oxide synthase and cyclooxygenase-2. Journal of Biological Chemistry, 283(6), 3077-3087.
[19] Slomiany, B.L. and 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(6), 245-253.
[20] Slomiany, B.L. and Slomiany, A. (2004) Platelet-activa- ting factor mediates H. pylori lipopolysaccharide interference with gastric mucin synthesis. IUBMB Life, 56(1), 41-46.
[21] Wagner, D.A., Glogowski, J., Skipper, P.L., Wishnok, J.S. and Tannenbaum, S.R. (1982) Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Journal of Analytical Biochemistry, 126(1), 131-138.
[22] Jaffrey, S.R., Erdjument-Bromage, H., Ferris, D., Tempst, P. and Snyder, S.H. (2001) Protein S-nitrosylation: A physiological signal for neuronal nitric acid. Nature Cell Biology, 3(2), 193-197.
[23] Forrester, M.T., Forrester, M.W. and Stamler, J.S. (2007) Assessment and application of the biotin switch technique for examining protein S-nitrosylation under conditions of pharmacologically induced oxidative stress. Journal of Biological Chemistry, 282(19), 13977-13983.
[24] Sapirstein, A. and Bonventre, J.V. (2000) Specific roles of phospholipase A2 as defined by gene knockout. Biochimica et Biophysica Acta, 1488(1-2), 139-148.
[25] Slomiany, B.L. and Slomiany, A. (2002) Nitric oxide as a modulator of gastric mucin synthesis: Role of ERK and p38 MAPK activation. IUBMB Life, 54(5), 267-273.
[26] Hirabayashi, T. and Shimizu, T. (2000) Localization and regulation of cytosolic phospholipase A2. Biochimica et Biophysica Acta, 1488(1-2), 124-138.

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