title: Neuron-specific prolyl-4-hydroxylase domain 2 knockout reduces brain injury after transient cerebral ischemia.
abstract: OBJECTIVE
  Numerous factors involved in the adaptive response to hypoxia, including erythropoietin and vascular endothelial growth factor are transcriptionally regulated by hypoxia-inducible factors (HIFs). During normoxia, prolyl-4-hydroxylase domain (PHD) proteins hydroxylate HIF-α subunits, resulting in their degradation. We investigated the effect of neuronal deletion of PHD2, the most abundant isoform in brain, for stroke outcome.
  
  
  METHODS
  We generated neuron-specific Phd2 knockout mice and subjected animals to systemic hypoxia or transient middle cerebral artery occlusion. Infarct volume and cell death were determined by histology. HIF-1α, HIF-2α, and HIF target genes were analyzed by immunoblotting and real-time polymerase chain reaction, respectively.
  
  
  RESULTS
  Neuron-specific ablation of Phd2 significantly increased protein stability of HIF-1α and HIF-2α in the forebrain and enhanced expression of the neuroprotective HIF target genes erythropoietin and vascular endothelial growth factor as well as glucose transporter and glycolysis-related enzymes under hypoxic and ischemic conditions. Mice with Phd2-deficient neurons subjected to transient cerebral ischemia exhibited a strong reduction in infarct size, and cell death of hippocampal CA1 neurons located in the peri-infarct region was dramatically reduced in these mice. Vessel density in forebrain subregions, except for caudate-putamen, was not altered in Phd2-deficient animals.
  
  
  CONCLUSIONS
  Our findings denote that the endogenous adaptive response on hypoxic-ischemic insults in the brain is at least partly dependent on the activity of HIFs and identify PHD2 as the key regulator for the protective hypoxia response. The results suggest that specific inhibition of PHD2 may provide a useful therapeutic strategy to protect brain tissue from ischemic injury.
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany. reiner.kunze@physiologie.uni-heidelberg.de
authors.forename: Reiner
authors.initials: R
authors.lastname: Kunze
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Roland
authors.initials: R
authors.lastname: Veltkamp
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.forename: Hugo H
authors.initials: HH
authors.lastname: Marti
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002544:Cerebral Infarction / Q000473:pathology; D005260:Female; D000860:Hypoxia / Q000150:complications; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D002546:Ischemic Attack, Transient / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009474:Neurons / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C490189:Egln1 protein, mouse