PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2

Sci Transl Med. 2014 May 14;6(236):236ra64. doi: 10.1126/scitranslmed.3008523.

Abstract

Radiation-induced gastrointestinal (GI) toxicity can be a major source of morbidity and mortality after radiation exposure. There is an unmet need for effective preventative or mitigative treatments against the potentially fatal diarrhea and water loss induced by radiation damage to the GI tract. We report that prolyl hydroxylase inhibition by genetic knockout or pharmacologic inhibition of all PHD (prolyl hydroxylase domain) isoforms by the small-molecule dimethyloxallyl glycine (DMOG) increases hypoxia-inducible factor (HIF) expression, improves epithelial integrity, reduces apoptosis, and increases intestinal angiogenesis, all of which are essential for radioprotection. HIF2, but not HIF1, is both necessary and sufficient to prevent radiation-induced GI toxicity and death. Increased vascular endothelial growth factor (VEGF) expression contributes to the protective effects of HIF2, because inhibition of VEGF function reversed the radioprotection and radiomitigation afforded by DMOG. Additionally, mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure. Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / chemistry
  • Animals
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors / chemistry*
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Body Weight
  • Cell Line, Tumor
  • Chelating Agents / chemistry
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / radiation effects
  • Gene Expression Regulation
  • Hematocrit
  • Heterozygote
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Mice
  • Mice, Knockout
  • Prolyl-Hydroxylase Inhibitors / chemistry
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Structure, Tertiary
  • Radiation Injuries / drug therapy*
  • Radiation Injuries / prevention & control
  • Vascular Endothelial Growth Factor A / chemistry

Substances

  • Amino Acids, Dicarboxylic
  • Basic Helix-Loop-Helix Transcription Factors
  • Chelating Agents
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Prolyl-Hydroxylase Inhibitors
  • Protein Isoforms
  • Vascular Endothelial Growth Factor A
  • endothelial PAS domain-containing protein 1
  • oxalylglycine