Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons.
The endoplasmic reticulum (ER), which plays a role in apoptosis, is susceptible to oxidative stress. Because superoxide is produced in the brain after ischemia/reperfusion, oxidative injury to this organelle may be implicated in ischemic neuronal cell death. Activating transcription factor-4 (ATF-4) and C/EBP-homologous protein (CHOP), both of which are involved in apoptosis, are induced by severe ER stress. Using wild-type and human copper/zinc superoxide dismutase transgenic rats, we observed induction of these molecules in the brain after global cerebral ischemia and compared them with neuronal degeneration. In ischemic, wild-type brains, expression of ATF-4 and CHOP was increased in the hippocampal CA1 neurons that would later undergo apoptosis. Transgenic rats had a mild increase in ATF-4 and CHOP and minimal neuronal degeneration, indicating that superoxide was involved in ER stress-induced cell death. We further confirmed attenuation on induction of these molecules in transgenic mouse brains after focal ischemia. When superoxide was visualized with ethidium, signals for ATF-4 and superoxide overlapped in the same cells. Moreover, lipids in the ER were robustly peroxidized by ischemia but were attenuated in transgenic animals. This indicates that superoxide attacked and damaged the ER, and that oxidative ER damage is implicated in ischemic neuronal cell death.
Hayashi
Takeshi
T
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5487, USA.
Saito
Atsushi
A
Okuno
Shuzo
S
Ferrand-Drake
Michel
M
Dodd
Robert L
RL
Chan
Pak H
PH
D051701:Activating Transcription Factor 4; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism
C497110:Atf4 protein, rat; D022762:CCAAT-Enhancer-Binding Proteins; C497251:Ddit3 protein, rat; D014157:Transcription Factors; D013481:Superoxides; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D013482:Superoxide Dismutase