X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants.
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.
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, Box 432, SE 405 30 Göteborg, Sweden.
Changlian
C
Zhu
Falin
F
Xu
Aya
A
Fukuda
Xiaoyang
X
Wang
Hirotsugu
H
Fukuda
Laura
L
Korhonen
Henrik
H
Hagberg
Birgitta
B
Lannering
Michael
M
Nilsson
Peter S
PS
Eriksson
Frances J
FJ
Northington
Thomas
T
Björk-Eriksson
Dan
D
Lindholm
Klas
K
Blomgren
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000528:radiation effects*; D002545:Brain Ischemia / Q000378:metabolism*; D045304:Cytochromes c / Q000037:antagonists & inhibitors; D005260:Female; D015870:Gene Expression; D002534:Hypoxia, Brain / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D000447:Aldehydes; D000975:Antioxidants; D051636:X-Linked Inhibitor of Apoptosis Protein; C002744:3-nitrotyrosine; D014443:Tyrosine; D045304:Cytochromes c; C027576:4-hydroxy-2-nonenal