Gastric mucosal protection via enhancement of MUC5AC and MUC6 by geranylgeranylacetone.

The mucus layer that covers gastric mucosa is a powerful barrier that protects tissues from the hazardous gastric environment; however, the role of each gastric MUC type, such as MUC1, MUC5AC, and MUC6, has not been evaluated. The purpose of this study is to identify the MUC type, which plays a predominant role in this protective process by use of geranylgeranylacetone (GGA), a promising cytoprotective agent. In addition, the mechanism of mucus secretion promoted by GGA was investigated. Rat gastric mucosal damage was provoked using ethanol, and GGA was pretreated 1 hour before ethanol. GGA was found to significantly protect rats from ethanol-induced gastric damage by increasing mucus levels, MUC5AC and MUC6, especially at ethanol-induced ulcer margins, but not by MUC1. When expression of heat shock protein 70 (HSP70) and neuronal nitric oxide synthase (nNOS) was evaluated by Western blotting, both were found to be increased in GGA-treated ethanol rats. In addition, the cytoprotective effect of GGA was blocked by L-NMMA, a nonspecific NOS inhibitor, but not blocked by aminoguanidine, a specific inducible nitric oxide synthase inhibitor, thus indicating the participation of nNOS. In conclusion, GGA protected ethanol-induced gastric damage by upregulating MUC5AC and MUC6 rather than MUC1. In addition, HSP70 and nNOS were found to be involved in GGA cytoprotection, probably by increasing mucus production or secretion.