Ghrelin suppression of Helicobacter pylori-induced S-nitrosylation-dependent Akt inactivation exerts modulatory influence on gastric mucin synthesis

Abstract

Loss of mucus coat integrity and the impairment in its mucin component as well as the disturbance in nitric oxide (NO) generation are well-recognized features of gastric disease associated with H. pylori infection. As ghrelin plays a major role in the regulation of nitric oxide synthase system, we investigated the influence of this hormone on H. pylori LPS-induced interference with gastric mucin synthesis. The results revealed that the LPS-induced impairment in mucin synthesis and accompanied induction in inducible nitric oxide synthase (iNOS) expression, were associated with the suppression in Akt kinase activity and the impairment in constitutive nitric oxide synthase (cNOS) phosphorylation. The LPS effect on Akt inactivation was manifested in the kinase protein S-nitrosylation and a decrease in its phosphorylation at Ser(473). Further, we show that the countering effect of ghrelin, on the LPS-induced impairment in mucin synthesis was reflected in the suppression of iNOS and the increase in Akt activation, associated with the loss in S-nitrosylation and the increase in phosphorylation, as well as cNOS activation through phosphorylation. Our findings demonstrate that up-regulation in iNOS with H. pylori infection and subsequent Akt kinase inactivation through S-nitrosylation exerts the detrimental effect on the processes dependent on Akt activation, including that of cNOS activation and mucin synthesis. We also show that ghrelin protection against H. pylori-induced impairment in mucin synthesis is intimately linked to the events of Akt activation and reflected in a decrease in the kinase S-nitrosylation and the increase in its phosphorylation.