1. Academic Validation
  2. 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

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

  • Biochem Biophys Res Commun. 2014 Jan 17;443(3):1008-13. doi: 10.1016/j.bbrc.2013.12.081.
Soohwan Yum 1 Huijeong Park 1 Sungchae Hong 1 Seongkeun Jeong 1 Wooseong Kim 1 Yunjin Jung 2
Affiliations

Affiliations

  • 1 College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
  • 2 College of Pharmacy, Pusan National University, Busan 609-735, South Korea. Electronic address: jungy@pusan.ac.kr.
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.

Keywords

Colitis; HIF prolyl hydroxylase; Hypoxia-inducible factor; N-(2-mercaptopropionyl)-glycine.

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