期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 68, 期 12, 页码 1326-1338出版社
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e3181c3b9be
关键词
Apoptosis; Apoptosis-inducing factor; BNIP3; Hypoxia
资金
- UAB Neuroscience Core Facilities [NS47466, NS57098]
- UAB Civitan International Research Center
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS041962, P30NS057098, R01NS035107, P30NS047466] Funding Source: NIH RePORTER
Perinatal hypoxia-ischemia may result in long-term neurological deficits. In addition to producing neuron death, HI causes death of neural precursor cells (NPCs) in the developing brain. To characterize the molecular pathways that regulate hypoxia-induced death of NPCs, we treated a mouse neural stein cell line (C 17.2 cells) and fibroblastic growth factor II-expanded primary NPCs derived from wild-type or gene-disrupted mice, with oxygen glucose deprivation or the hypoxia mimetics desferrioxamine or cobalt chloride. Neural precursor cells undergoing hypoxia exhibited time- and concentration-dependent caspase-3 activation and cell death, which was significantly reduced by treatment with a broad caspase inhibitor or protein synthesis inhibition. Bax/Bak-deficient NPCs were protected from desferrioxamine-induced death and exhibited minimal caspase-3 activation. Oxygen glucose deprivation or hypoxia-mimetic exposure also resulted in increased hypoxia-inducible factor (x and bcl-2/adenovirus E1B 19-kd interacting protein 3 (BNIP3) expression. BNIP3 shRNA treatment failed to affect hypoxia-induced caspase-3 activation but inhibited cell death and nuclear translocation of apoptosis-inducing factor, indicating that BNIP3 is an important regulator of caspase-independent NPC death after hypoxia. These studies demonstrate that hypoxia activates both caspase-dependent and -independent NPC death pathways that are critically regulated by multiple Bcl-2 family members.
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