期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 25, 期 1, 页码 41-53出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600005
关键词
cell death; endoplasmic reticulum; lipid peroxidation; oxidative stress; superoxide dismutase; transcription factor
资金
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS025372, R01NS036147, P01NS037520, R01NS038653, P50NS014543] Funding Source: NIH RePORTER
- NINDS NIH HHS [R01 NS36147, P01 NS37520, R01 NS38653, P50 NS14543, R01 NS25372] Funding Source: Medline
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 Ell and that oxidative ER damage is implicated in ischemic neuronal cell death.
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