Increased heat-shock protein 90 expression contributes to impaired adaptive cytoprotection in the gastric mucosa of portal hypertensive rats.

Background And Aims: Portal hypertensive (PHT) gastropathy results in an increased susceptibility to damage. Adaptive cytoprotection against ethanol-induced damage is impaired in the gastric mucosa of rats with portal hypertension. Excessive nitric oxide (NO) production occurs in portal hypertension and is mediated in part via heat-shock protein (Hsp)90 production. The aim of this study was to investigate the relation between adaptive cytoprotection after exposure to ethanol and gastric expression of Hsp90 in PHT rats.

Methods: Portal hypertension was induced in rats by staged portal vein occlusion. Adaptive cytoprotection to 70% ethanol was evaluated by assessing the injury index of the gastric mucosa with or without pretreatment with 10% ethanol. Expression of Hsp90 mRNA was evaluated by real-time polymerase chain reaction, and expression of Hsp90 protein was evaluated by western blotting. The effect of Hsp90 inhibition in PHT rats was evaluated by administration of geldanamycin.

Results: Gastric Hsp90 mRNA expression in PHT rats was significantly less than that in sham-operated (SO) controls. However, after 10% ethanol pretreatment, Hsp90 mRNA expression was significantly greater in PHT rats than in SO controls. In PHT rats, gastric Hsp90 protein expression after 10% ethanol pretreatment was significantly greater than that without the pretreatment. However, the pretreatment had no effect on the injury index compared to SO rats. Administration of geldanamycin prior to 10% ethanol pretreatment significantly decreased the injury index in response to 70% ethanol in the PHT rats.

Conclusions: These results show that 10% ethanol pretreatment markedly increases gastric Hsp90 expression in PHT rats. Excessive production of Hsp90 may contribute impaired adaptive cytoprotection.