X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants

Changlian Zhu, Falin Xu, Aya Fukuda, Xiaoyang Wang, Hirotsugu Fukuda, Laura Korhonen, Henrik Hagberg, Birgitta Lannering, Michael Nilsson, Peter S. Eriksson, Frances J. Northington, Thomas Björk-Eriksson, Dan Lindholm, Klas Blomgren

Research output: Contribution to journalArticlepeer-review

Abstract

We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.

Original languageEnglish (US)
Pages (from-to)3402-3410
Number of pages9
JournalEuropean Journal of Neuroscience
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2007

Keywords

  • Irradiation
  • Ischemia
  • Mouse
  • Superoxide dismutase
  • Thioredoxin

ASJC Scopus subject areas

  • Neuroscience(all)

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