Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP.
Brain ischemia induces apoptosis in neuronal cells, but the mechanism is not well understood. When wild-type mice were subjected to bilateral common carotid arteries occlusion (BCCAO) for 15 min, apoptosis-associated morphological changes and appearance of TUNEL-positive cells were observed in the striatum and in the hippocampus at 48 h after occlusion. RT-PCR analysis revealed that mRNAs for ER stress-associated proapoptotic factor CHOP and an ER chaperone BiP are markedly induced at 12 h after BCCAO. Immunohistochemical analysis showed that CHOP protein is induced in nuclei of damaged neurons at 24 h after occlusion. In contrast, ischemia-associated apoptotic loss of neurons was decreased in CHOP(-/-) mice. Primary hippocampal neurons from CHOP(-/-) mice were more resistant to hypoxia-reoxygenation-induced apoptosis than those from wild-type animals. These results indicate that ischemia-induced neuronal cell death is mediated by the ER stress pathway involving CHOP induction.
Tajiri
S
S
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. yanos@kaiju.medic.kumamoto-u.ac.jp
Oyadomari
S
S
Yano
S
S
Morioka
M
M
Gotoh
T
T
Hamada
J I
JI
Ushio
Y
Y
Mori
M
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017536:Carotid Artery, Common / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D014157:Transcription Factors; D051742:Transcription Factor CHOP