Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Death
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genes, Reporter
  • Hemin
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Iron
  • Iron Chelating Agents
  • Mice
  • Neuroprotective Agents
  • Protein Domains
  • Protein Isoforms
  • Rats
  • Recovery of Function

MeSH Major

  • Activating Transcription Factor 4
  • Brain
  • Intracranial Hemorrhages
  • Molecular Targeted Therapy
  • Neurons
  • Oxygen
  • Procollagen-Proline Dioxygenase

abstract

  • Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models. Copyright © 2016, American Association for the Advancement of Science.

authors

publication date

  • March 2, 2016

has subject area

  • Activating Transcription Factor 4
  • Animals
  • Brain
  • Cell Death
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genes, Reporter
  • Hemin
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intracranial Hemorrhages
  • Iron
  • Iron Chelating Agents
  • Mice
  • Molecular Targeted Therapy
  • Neurons
  • Neuroprotective Agents
  • Oxygen
  • Procollagen-Proline Dioxygenase
  • Protein Domains
  • Protein Isoforms
  • Rats
  • Recovery of Function

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5341138

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aac6008

PubMed ID

  • 26936506

Additional Document Info

start page

  • 328ra29

volume

  • 8

number

  • 328