Nitric oxide induces HIF-1alpha stabilization and expression of intestinal trefo

2011-06-21 MedSci原创 MedSci原创

NitricoxideHIF-1alphaintestinaltrefoilfactor

Riano, A., D. Ortiz-Masia, et al. (2011). "Nitric oxide induces HIF-1alpha stabilization and expression of intestinal trefoil factor in the damaged rat jejunum and modulates ulcer healing." J Gastroen

Riano, A., D. Ortiz-Masia, et al. (2011). "Nitric oxide induces HIF-1alpha stabilization and expression of intestinal trefoil factor in the damaged rat jejunum and modulates ulcer healing." J Gastroenterol 46(5): 565-576.

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-1alpha 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-1alpha, ITF and nitrated proteins was observed in the injured jejunum. Immunoprecipitation of HIF-1alpha 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-1alpha stabilization and HIF-1alpha 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-1alpha stabilization, probably through S-nitrosylation, and ITF expression in goblet cells of the damaged jejunum of indomethacin-treated rats and mediates ulcer healing.



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