title: Hypoxic preconditioning involves system Xc- regulation in mouse neural stem cells.
abstract: In animals, hypoxic preconditioning has been used as a form of neuroprotection. The exact mechanism involved in neuroprotective hypoxic preconditioning has not been described, yet could be valuable for possible neuroprotective strategies. The overexpression of the cystine-glutamate exchanger, system Xc-, has been demonstrated as being neuroprotective (Shih, Erb et al. 2006). Here, using immunohistochemistry, we demonstrate that C57BL/6 mice exposed to hypoxia showed an increase in system Xc- expression, with the highest level of intensity in the hippocampus. Western Blot analysis also showed an almost 2-fold increase in system Xc- protein in hypoxia-exposed versus control mice. The mRNA for the regulatory subunit of system Xc-, xCT, and the xCT/actin ratio were also increased under hypoxic conditions. Experiments using hypoxia-inducible factor (HIF-1α) siRNA showed a statistically significant decrease in HIF-1α and system Xc- expression. Under hypoxic conditions, system Xc- activity, as determined by cystine uptake, increased 2-fold. Importantly, hypoxic preconditioning was attenuated in neural stem cells by pharmacological inhibition of system Xc- activity with S4-carboxyphenylglycine. These data provide the first evidence of hypoxic regulation of the cystine glutamate exchanger system Xc-.
authors: Department of Pediatrics, University of Alabama at Birmingham, 35294, USA. bsims@peds.uab.edu
authors: Brian
authors: B
authors: Sims
authors: Melinda
authors: M
authors: Clarke
authors: Ludwig
authors: L
authors: Francillion
authors: Elijah
authors: E
authors: Kindred
authors: Elana Shuford
authors: ES
authors: Hopkins
authors: Harald
authors: H
authors: Sontheimer
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000378:metabolism; D015687:Cell Hypoxia; D003553:Cystine / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D027182:Amino Acid Transport System y+; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C492255:Slc7a11 protein, mouse; D003553:Cystine