Nitric oxide as a modulator of gastric mucin synthesis: role of ERK and p38 mitogen-activated protein kinase activation.
Nitric oxide (NO) is an important biological messenger in the regulation of tissue homeostasis and pathophysiological processes. Here, we investigated the effect of NO on gastric mucus glycoprotein (mucin) synthesis, apoptotic processes, and the involvement of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Exposure of gastric mucosal cells to NO donor led to a dose-dependent decrease (up to 48%) in mucin synthesis, accompanied by a marked increase in caspase-3 activity and apoptosis. Inhibition of ERK with PD98059 accelerated (up to 23.8%) the NO-induced decrease in mucin synthesis, and cause further enhancement in caspase-3 activity and apoptosis. Blockade of p38 kinase with SB203580 produced reversal in the NO-induced reduction in mucin synthesis, and substantially countered the induced increase in caspase-3 activity and apoptosis. Moreover, caspase-3 inhibitor not only blocked the NO-induced increase in caspase-3 activity but also produced an increase in mucin synthesis. Thus, the detrimental influence of NO on mucin synthesis is closely linked to caspase-3 activation and apoptosis, and involves ERK and p38 kinase participation. Activation of p38 kinase leads to the upregulation of proapoptotic signal, while ERK activation stimulates the anti-apoptotic pathway.
Slomiany
Bronislaw L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Dental School, Newark, New Jersey 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009077:Mucins / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism; D009092:Mucous Membrane / Q000166:cytology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009077:Mucins; D020030:Nitric Oxide Donors; D011725:Pyridines; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one