Constitutive nitric oxide synthase-mediated caspase-3 S-nitrosylation in ghrelin protection against Porphyromonas gingivalis-induced salivary gland acinar cell apoptosis.
Recent advances in identifying the salivary constituents capable of influencing the oral mucosal inflammatory responses have brought to focus the importance of a peptide hormone, ghrelin. Here, we report on the involvement of ghrelin in controlling the apoptotic processes induced in sublingual salivary gland acinar cells by the lipopolysaccharide (LPS) of a periodontopathic bacterium, Porphyromonas gingivalis. We show that the countering effect of ghrelin on the LPS-induced acinar cell apoptosis was associated with the increase in constitutive nitric oxide synthase (cNOS) activity, and the reduction in caspase-3 and inducible nitric oxide synthase (iNOS). The loss in countering effect of ghrelin on the LPS-induced changes in apoptosis and caspase-3 activity was attained with Src kinase inhibitor, PP2, as well as Akt inhibitor, SH-5, and cNOS inhibitor, L-NAME, but not the iNOS inhibitor, 1400W. The effect of ghrelin on the LPS-induced changes in cNOS activity, moreover, was reflected in the increased cNOS phosphorylation that was sensitive to PP2 as well as SH-5. Furthermore, the ghrelin-induced up-regulation in cNOS activity was associated with the increase in caspase-3 S-nitrosylation that was susceptible to the blockage by SH-5 and L-NAME. The findings point to the involvement of ghrelin in Src/Akt kinase-mediated cNOS activation and the apoptogenic signal inhibition through the NO-induced caspase-3 S-nitrosylation.
Research Center, C875, UMDNJ-NJ Dental School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
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D000578:Amidines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054439:Ghrelin / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016966:Porphyromonas gingivalis / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D026403:S-Nitrosothiols / Q000378:metabolism*; D013361:Sublingual Gland / Q000166:cytology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
C435044:1-((1-O-octadecyl-2-O-methylglycero)phospho)-3-deoxy-myo-inositol; C412373:AG 1879; D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D054439:Ghrelin; D007295:Inositol Phosphates; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D026403:S-Nitrosothiols; C021315:S-nitrosocysteine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D003545:Cysteine; D001205:Ascorbic Acid; D019331:NG-Nitroarginine Methyl Ester