title: Dimethyloxalyglycine stimulates the early stages of gastrointestinal repair processes through VEGF-dependent mechanisms.
abstract: Dimethyloxalylglycine (DMOG) is an inhibitor of prolyl-4-hydroxylase domain enzymes. Its potential value and mechanism of actions in preventing/treating gastrointestinal injury are, however, poorly understood. We, therefore, examined the effect of DMOG on influencing gut injury and repair using a variety of in vitro and in vivo models. We performed in vitro studies utilising pro-migratory (wounded monolayer) and proliferation (using DNA quantitation) assays of human stomach (AGS) and colonic (HT29) carcinoma cells. Time course studies examined changes in hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF) levels, a growth factor known to be regulated via HIF. In vivo studies utilised a rat gastric (indomethacin, 20 mg/kg and 3 h restraint) damage model. DMOG stimulated migration in a dose-dependent manner, increasing migration twofold when added at 25μM (P<0.01). Additive effects were seen when DMOG was added to cells in hypoxic conditions. DMOG stimulated proliferation dose dependently, increasing proliferation threefold when added at 70 μM (P<0.01). DMOG caused upregulation of both HIF and VEGF within 4 h of administration. Addition of VEGF neutralising antibody truncated migratory and proliferative activity of DMOG by about 70%. Both oral and subcutaneous administration of DMOG decreased gastric injury without influencing intragastric pH (50% reduction in injury when 1 ml gavaged at 0.57 mM, P < 0.01). Indomethacin reduced tissue HIF and VEGF levels but this was prevented if DMOG was present. In conclusion, DMOG stimulates the early phases of gut repair and VEGF-dependent processes appear relevant. Non-peptide factors such as this may be useful to stabilise or repair gut mucosa.
authors.affiliation: Faculty of Health Science, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Tania
authors.initials: T
authors.lastname: Marchbank
authors.forename: Asif
authors.initials: A
authors.lastname: Mahmood
authors.forename: Sarah
authors.initials: S
authors.lastname: Harten
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Playford
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D019073:HT29 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000600:Amino Acids, Dicarboxylic; D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C040947:oxalylglycine