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J Gastroenterol. 2011 May;46(5):565-76. doi: 10.1007/s00535-011-0374-1. Epub 2011 Feb 9.

Nitric oxide induces HIF-1α stabilization and expression of intestinal trefoil factor in the damaged rat jejunum and modulates ulcer healing.

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  • 1Department of Pharmacology and CIBERehd, Faculty of Medicine, University of Valencia, Avda. Blasco Ibanez 15-17, 46010 Valencia, Spain.

Abstract

BACKGROUND:

The induction of intestinal trefoil factor (ITF) has been reported to depend on hypoxia-inducible factor-1 (HIF-1). Nitric oxide modulates HIF-1 activity. The present study aims to analyze the role of nitric oxide in jejunum damage induced by indomethacin and its ability to modulate epithelial function through the expression of ITF.

METHODS:

Rats received indomethacin (7.5 mg/kg, s.c., twice), and a time course analysis of damage was performed (24-96 h after the first administration). In these animals, the role of nitric oxide was analyzed by using 1400W, a selective iNOS activity inhibitor (5 mg/kg, i.p./day), on: (1) intestinal damage, (2) ulcer healing, (3) the presence of nitrated proteins in the jejunum and (4) the protein expression of inducible nitric oxide synthase (iNOS), HIF-1α and ITF.

RESULTS:

Indomethacin induced damage in the jejunum that was apparent at 24 h and peaked at 48-72 h. An increase in iNOS, HIF-1α, ITF and nitrated proteins was observed in the injured jejunum. Immunoprecipitation of HIF-1α allowed determination of the nitration/nitrosylation of this protein by using nitrotyrosine and nitrocysteine antibodies. Blockade of iNOS activity did not significantly modify damage or iNOS expression, but did significantly impede ITF induction, HIF-1α stabilization and HIF-1α detection with antibodies against nitrated proteins. In parallel to these results, pre-treatment with 1400W delayed the healing of the ulcer provoked by indomethacin.

CONCLUSIONS:

These results suggest that iNOS-derived NO is involved in HIF-1α stabilization, probably through S-nitrosylation, and ITF expression in goblet cells of the damaged jejunum of indomethacin-treated rats and mediates ulcer healing.

PMID:
21305324
[PubMed - indexed for MEDLINE]
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