The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis.

Abstract

BACKGROUND & AIMS:

Prolyl and asparaginyl hydroxylases are key oxygen-sensing enzymes that confer hypoxic sensitivity to transcriptional regulatory pathways including the hypoxia inducible factor 1 (HIF-1) and nuclear factor-kappaB (NF-kappaB). Knockout of either HIF-1 or (IKKbeta-dependent) NF-kappaB pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappaB pathways are repressed by the action of hydroxylases through the hydroxylation of key regulatory molecules.

METHODS:

In this study we have investigated the effects of the hydroxylase inhibitor dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial cells in vitro and in a dextran sodium sulfate-induced model of murine colitis.

RESULTS:

DMOG induces both HIF-1 and NF-kappaB activity in cultured intestinal epithelial cells, and is profoundly protective in dextran-sodium sulfate colitis in a manner that is at least in part reflected by the development of an anti-apoptotic phenotype in intestinal epithelial cells, which we propose reduces epithelial barrier dysfunction.

CONCLUSIONS:

These data show that hydroxylase inhibitors such as DMOG represent a new strategy for the treatment of inflammatory bowel disease.

• Authors: Eoin P Cummins, Fergal Seeballuck, Stephen J Keely, Niamh E Mangan, John J Callanan, Padraic G Fallon, Cormac T Taylor
• Journal: Gastroenterology (Gastroenterology) Vol. 134 Issue 1 Pg. 156-65 (Jan 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18166353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids, Dicarboxylic
• Enzyme Inhibitors
• Hypoxia-Inducible Factor 1, alpha Subunit
• NF-kappa B
• Mixed Function Oxygenases
• oxalylglycine

Topics

• Amino Acids, Dicarboxylic (pharmacology, therapeutic use)
• Animals
• Caco-2 Cells (drug effects, metabolism)
• Cell Culture Techniques
• Colitis (metabolism, pathology, prevention & control)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mice, Inbred C57BL
• Mixed Function Oxygenases (antagonists & inhibitors)
• NF-kappa B (metabolism)