Details

Autor(en) / Beteiligte

• Yum, Soohwan
• Park, Huijeong
• Hong, Sungchae
• Jeong, Seongkeun
• Kim, Wooseong
• Jung, Yunjin

Titel

N-(2-mercaptopropionyl)-glycine, a diffusible antioxidant, activates HIF-1 by inhibiting HIF prolyl hydroxylase-2: Implication in amelioration of rat colitis by the antioxidant

Ist Teil von

• Biochemical and biophysical research communications, 2014-01, Vol.443 (3), p.1008-1013

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• •N-(2-mercaptopropionyl)-glycine (NMPG), a diffusible anti-oxidant, ameliorates TNBS-induced rat colitis.•NMPG activates an ulcer healing pathway, HIF-1-VEGF.•NMPG stabilizes HIF-1α protein by inhibiting HIF prolyl hydroxylase-2 (HPH-2).•NMPG inhibition of HPH-2 is attenuated by ascorbate, a cofactor of the enzyme. We investigated anti-colitic effects of N-(2-mercaptopropionyl)-glycine (NMPG), a diffusible antioxidant, in TNBS-induced rat colitis model and a potential molecular mechanism underlying the pharmacologic effect of the antioxidant. NMPG alleviated colonic injury and effectively lowered myeloperoxidase activity. Moreover, NMPG substantially attenuated expression of pro-inflammatory mediators in the inflamed colon. NMPG induced hypoxia-inducible factor-1α (HIF-1α) in human colon carcinoma cells, leading to elevated secretion of vascular endothelial growth factor (VEGF), a target gene product of HIF-1 involved in ulcer healing of gastrointestinal mucosa. NMPG induction of HIF-1α occurred by inhibiting HIF prolyl hydroxylase-2 (HPH-2), an enzyme that plays a major role in negatively regulating HIF-1α protein stability. In in vitro Von Hippel-Lindau protein binding assay, the inhibitory effect of NMPG on HPH-2 was attenuated by escalating dose of ascorbate but not 2-ketoglutarate, cofactors of the enzyme. Consistent with this, cell-permeable ascorbate significantly attenuated NMPG induction of HIF-1α in cells. Our data suggest that NMPG is an anti-colitic antioxidant that exerts its pharmacologic effects at least partly through activation of an ulcer healing pathway, HIF-1-VEGF.