Nitric oxide interferes with salivary mucin synthesis: involvement of ERK and p38 mitogen-activated protein kinase.
BACKGROUND
Nitric oxide (NO), a pluripotent molecule, is an important biological messenger that plays a role in the regulation of tissue homeostasis and pathophysiological processes.


METHODS
Using sublingual salivary gland acinar cells in culture, we investigated the effect of NO on mucus glycoprotein synthesis, apoptotic processes, and the involvement of extracellular signal-regulated kinase (ERK) and p38 mitogen activated protein kinase (MAPK).


RESULTS
Exposure of the acinar cells to NO donor led to a dose-dependent decrease (up to 42.8%) in mucus glycoprotein synthesis, and this effect of NO was accompanied by a marked increase in caspase-3 activity and apoptosis. Inhibition of ERK with PD98059 accelerated (up to 35.4%) the NO-induced decrease in the glycoprotein synthesis, and cause further enhancement in caspase-3 (up to 27.2%) activity and apoptosis (64.9%). On the other hand, blockade of p38 kinase with SB203580 produced a dose-dependent reversal (up to 42%) in the NO-induced reduction in the glycoprotein synthesis, and substantially countered the NO-induced increases in caspase-3 activity (by 62.8%) and apoptosis (by 57.6%). Moreover, caspase-3 inhibitor, Ac-DEVD-CHO, not only blocked the NO-induced increase in caspase-3 activity but also produced an increase in the glycoprotein synthesis.


CONCLUSIONS
Together, our data indicate that the modulatory influence of NO on salivary mucin synthesis is closely linked to ERK and p38 protein kinase activation, in conjunction with caspase-3 activation and apoptosis.
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006023:Glycoproteins / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009077:Mucins / Q000096:biosynthesis*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000008:administration & dosage; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013361:Sublingual Gland / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006023:Glycoproteins; D007093:Imidazoles; D009077:Mucins; D020030:Nitric Oxide Donors; D009842:Oligopeptides; D011725:Pyridines; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C047874:gastric mucus glycoproteins; D009599:Nitroprusside; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one