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Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent
R Kinscherf1, R Claus, M Wagner
1Department of Anatomy and Cell Biology III, University of Heidelberg, Germany.
Abstract:
Oxidized low density lipoprotein (oxLDL) induces apoptosis in human macrophages (Mphi), a significant feature in atherogenesis. We found that induction of apoptosis in Mphi by oxLDL, C2-ceramide, tumor necrosis factor alpha (TNF-alpha), and hydrogen peroxide (H2O2) was associated with enhanced expression of manganese superoxide dismutase (MnSOD) and p53. Treatment of cells with p53 or MnSOD antisense oligonucleotides prior to stimulation with oxLDL, C2-ceramide, TNF-alpha, or H2O2 caused an inhibition of the expression of the respective protein together with a marked reduction of apoptosis. Exposure to N-acetylcysteine before treatment with oxLDL, C2-ceramide, TNF-alpha, or H2O2 reversed a decrease in cellular glutathione concentrations as well as the enhanced production of p53 and MnSOD mRNA and protein. In apoptotic macrophages of human atherosclerotic plaques, colocalization of MnSOD and p53 immunoreactivity was found. These results indicate that in oxLDL-induced apoptosis, a concomitant induction of p53 and MnSOD is critical, and suggest that it is at least in part due to an enhancement of the sphingomyelin/ceramide pathway.
Insights
Oxidized low density lipoprotein (oxLDL) triggers apoptosis in human macrophages by upregulating manganese superoxide dismutase (MnSOD) and p53. Inhibiting these proteins reduces oxLDL-induced cell death, suggesting a key role in atherosclerosis.
Area of Science:
- Cell Biology
- Biochemistry
- Pathology
Background:
- Oxidized low density lipoprotein (oxLDL) is implicated in atherogenesis.
- Macrophage apoptosis is a significant feature of atherosclerosis.
Purpose of the Study:
- To investigate the role of manganese superoxide dismutase (MnSOD) and p53 in oxLDL-induced macrophage apoptosis.
- To explore the involvement of the sphingomyelin/ceramide pathway.
Main Methods:
- Utilized antisense oligonucleotides to inhibit p53 and MnSOD expression.
- Assessed apoptosis induction by oxLDL, C2-ceramide, TNF-alpha, and H2O2.
- Measured cellular glutathione levels and mRNA/protein expression.
- Examined immunoreactivity in macrophages from atherosclerotic plaques.
Main Results:
- Apoptosis induced by oxLDL, C2-ceramide, TNF-alpha, and H2O2 correlated with increased MnSOD and p53 expression.
- Inhibition of p53 or MnSOD significantly reduced apoptosis.
- N-acetylcysteine treatment restored glutathione levels and reduced p53/MnSOD production.
- Colocalization of MnSOD and p53 was observed in apoptotic macrophages from atherosclerotic plaques.
Conclusions:
- Concomitant induction of p53 and MnSOD is critical for oxLDL-induced macrophage apoptosis.
- The sphingomyelin/ceramide pathway appears to be involved in this process.
- Targeting p53 and MnSOD may offer therapeutic strategies for atherosclerosis.