期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 53, 期 11, 页码 2054-2061出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.09.007
关键词
Apoptosis; Atherosclerosis; Bax; Lysosomes; Mitochondria; Oxidative stress; Free radicals
资金
- Swedish Heart Lung Foundation
- Torsten and Ragnar Soderbergs Foundation
- Stroke Foundation
- Olle Engkvist Foundation
- Swedish Gamla Tjanarinnor Foundation
- Linkoping University
- Linkoping University Hospital
Oxysterol accumulation and p53 expression mainly in macrophages have been associated with cell death and necrotic core formation in human atheroma progression. Oxidative stress and lysosomal membrane permeabilization (LMP) in macrophages are important causes of macrophage apoptosis. However, it is not understood how p53 and oxysterols interact in the process. We show here that 7-oxysterols induce endogenous full-length p53 and phospho-p53 (p53-Ser15) in both nucleus and cytoplasm of THP1 and J774 cells, which is followed by cellular oxidative stress and apoptotic cell death. The role of p53 in 7-oxysterol-mediated cell death is further investigated in temperature sensitive p53-transfected (M1-t-p53) and in p53-deficient (M1) cells. These results reveal that 7-oxysterols induce induction and nuclear translocation of p53 in M1-t-p53 cells, which in turn enhances LMP, mitochondrial translocation of Bax, mitochondrial membrane permeabilization, cytosolic release of cytochrome c, and cell death. Most importantly, the above effects of 7-oxysterols were not observed in p53-deficient M1 cells. The findings reveal that 7-oxysterol-induced cell death occurs via p53-dependent pathways. Subsequent p53 nuclear translocation and induction of wild-type and phosphorylated p53 are early steps in oxysterol-induced lysosomal-mitochondrial pathways involved in cell death. (C) 2012 Elsevier Inc. All rights reserved.
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