Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 30, Issue 8, Pages 884-894Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0891-5849(01)00476-2
Keywords
4-hydroxy-2-nonenal; apoptosis; p53 tumor suppressor; cytochrome c; bcl-2; p21(WAF1/CTP1); SV-40 T-antigen; lipid peroxidation; DNA fragmentation; free radicals
Funding
- NCI NIH HHS [P30-CA-12197-26, R01-CA-76283] Funding Source: Medline
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The toxic reactive aldehyde lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE) is thought to be a major contributor to oxidant stress-mediated cell injury. HNE induced apoptosis in RAW 264.7 murine macrophage cells in a dose-dependent manner within 6-8 h after exposure. Expression of the antiapoptotic protein Bcl-2 in stably transfected RAW 264.7 cells prevented HNE-induced internucleosomal DNA fragmentation and apoptosis. and these cells resume growth after a temporary (24-48 h) growth delay. While parental RAW 264.7 cells released mitochondrial cytochrome c within 3 h after HNE exposure, expression of Bcl-2 prevented cytochrome c release. In control cells, p53 protein levels peaked at 6-9 h after HNE exposure and then declined, while in Bcl-2 expressing cells, p53 levels were maximal at 6-9 h and remained elevated up to 96 h. Expression of SV40 large T-antigen, which forms a stable complex with p53 protein, via stable transfection-blocked transactivation of the p53-regulated gene p21(WAF1/CIP1), hut did not affect induction of apoptosis by HNE. suggesting that p53 function is not important in HNE-induced apoptosis. These results suggest that cytochrome c release, but not p53 accumulation, plays an essential role in HNE-induced apoptosis in RAW 264.7 cells. (C) 2001 Elsevier Science Inc.
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