title: 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.
abstract: 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.
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Yum
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
authors.forename: Huijeong
authors.initials: H
authors.lastname: Park
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
authors.forename: Sungchae
authors.initials: S
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
authors.forename: Seongkeun
authors.initials: S
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, South Korea. Electronic address: jungy@pusan.ac.kr.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003092:Colitis / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004058:Diffusion; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D064828:Prolyl Hydroxylases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D008625:Tiopronin / Q000494:pharmacology / Q000627:therapeutic use*; D014302:Trinitrobenzenesulfonic Acid; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000975:Antioxidants; D001205:Ascorbic Acid; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064828:Prolyl Hydroxylases; D008625:Tiopronin; D014302:Trinitrobenzenesulfonic Acid; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: Colitis; HIF prolyl hydroxylase; Hypoxia-inducible factor; N-(2-mercaptopropionyl)-glycine