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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Semlitsch, M; Shackelford, RE; Zirkl, S; Sattler, W; Malle, E.
ATM protects against oxidative stress induced by oxidized low-density lipoprotein.
DNA Repair (Amst). 2011; 10(8):848-860
Doi: 10.1016/j.dnarep.2011.05.004
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- Führende Autor*innen der Med Uni Graz
- Malle Ernst
- Semlitsch Michaela
- Co-Autor*innen der Med Uni Graz
- Kickmaier Sandra
- Sattler Wolfgang
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- Abstract:
- Chronic oxidative stress is involved in the pathogenesis of multiple inflammatory diseases, including cardiovascular disease and atherosclerosis. The rare autosomal recessive disorder Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia secondary to Purkinje cell death, immunodeficiency, and increased cancer incidence. ATM, the protein mutated in A-T, plays a key role in cellular DNA-damage responses. A-T cells show poor cellular anti-oxidant defences and increased oxidant sensitivity compared to normal cells, and ATM functions, in part, as an oxidative stress sensor. The oxidation of low-density lipoprotein (oxLDL) and its uptake by macrophages is an initiating step in the development of atherosclerosis. We demonstrate that oxLDL activates ATM and downstream p21 expression in normal fibroblasts and endothelial cells. In ATM-deficient fibroblasts oxLDL induces DNA double-strand breaks, micronuclei formation and causes chromosome breaks. Furthermore, oxLDL decreases cell viability and inhibits colony formation in A-T fibroblasts more effectively as compared to normal controls. Formation of oxLDL-induced reactive oxygen species is significantly higher in A-T, than normal fibroblasts. Last, pre-treatment of cells with ammonium pyrrolidine dithiocarbamate, a potent antioxidant and inhibitor of transcription factor nuclear factor κB, reduces oxLDL-induced reactive oxygen species formation. Our data indicates that ATM functions in the defence against oxLDL-mediated cytotoxicity.
- Find related publications in this database (using NLM MeSH Indexing)
- Antioxidants - pharmacology
- Ataxia Telangiectasia Mutated Proteins -
- Cell Cycle Proteins - antagonists & inhibitors
- Cell Line -
- Cell Survival -
- Cyclin-Dependent Kinase Inhibitor p21 - metabolism
- DNA Breaks, Double-Stranded -
- DNA-Binding Proteins - antagonists & inhibitors
- Endothelial Cells - drug effects
- Fibroblasts - drug effects
- Gene Expression -
- Humans -
- Lipoproteins, LDL - metabolism
- Oxidative Stress -
- Phosphorylation -
- Protein Kinase Inhibitors - pharmacology
- Protein-Serine-Threonine Kinases - antagonists & inhibitors
- Pyrrolidines - pharmacology
- Reactive Oxygen Species - metabolism
- Thiocarbamates - pharmacology
- Tumor Suppressor Proteins - antagonists & inhibitors
- Find related publications in this database (Keywords)
- ROS
- Modified LDL
- DNA-double-strand breaks
- Atherosclerosis
- p21
- Colony forming efficiency assay
- EA.hy926 cells
- Hydrogen peroxide