Post-treatment with the Ca(2+)-Mg(2+)-endonuclease inhibitor aurintricarboxylic acid prevents peroxynitrite-induced DNA damage and death of murine astrocytes.
Oxidative stress plays critical roles in aging, cell death, and many diseases. Peroxynitrite is one of the major reactive oxygen species which mediates cell injury in a number of illnesses. It is of importance to identify the downstream events in peroxynitrite-initiated cell death cascade for preventing peroxynitrite toxicity. Ca(2+)-Mg(2+)-endonucleases have been suggested as the endonucleases that execute DNA fragmentation in several apoptotic cascades. In this study, we determined if astrocytes and neurons express the genes of Ca(2+)-Mg(2+)-endonucleases. We also tested our hypothesis that post-treatment with the Ca(2+)-Mg(2+)-endonuclease inhibitor aurintricarboxylic acid can decrease peroxynitrite-induced DNA damage and death of astrocytes. We found that both astrocytes and neurons express DNase I-like endonuclease-a major isoform of Ca(2+)-Mg(2+)-endonucleases. Treatment of astrocytes with aurintricarboxylic acid either before or after peroxynitrite exposures can profoundly decrease peroxynitrite-induced DNA damage and cell death. These results suggest that Ca(2+)-Mg(2+)-endonucleases may be a key downstream component in peroxynitrite-initiated cell death cascade in astrocytes and some other cell types, and aurintricarboxylic acid could be used to decrease peroxynitrite-induced DNA damage at delayed phases.
Zhu
Keqing
K
Department of Neurology, Veterans Affairs Medical Center, University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA.
Lu
Huafei
H
Ying
Weihai
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D001312:Aurintricarboxylic Acid / Q000008:administration & dosage*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004706:Endodeoxyribonucleases / Q000037:antagonists & inhibitors*; D051379:Mice; D030421:Peroxynitrous Acid / Q000633:toxicity*
D030421:Peroxynitrous Acid; D001312:Aurintricarboxylic Acid; D004706:Endodeoxyribonucleases; C029367:calcium magnesium dependent endodeoxyribonuclease