Journal
TOXICOLOGY IN VITRO
Volume 50, Issue -, Pages 29-39Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2018.02.001
Keywords
Isoproterenol; Chronic stress; PARP; DNA strand breaks; DNA repair
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Funding
- Young Scholar Fund from the Excellence Initiative at the University of Konstanz [83990812]
- CETICS GmbH [15982912]
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Psychological stress has been associated with DNA damage, thus increasing the risk of numerous diseases including cancer. Here, we investigate the effect of acute and chronic stress on poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage and DNA repair initiator. In order to mimic the chronic release of epinephrine, human peripheral blood mononuclear cells (PBMCs) were treated repeatedly with the sympathomimetic drug isoproterenol. We found significant induction of DNA strand breaks that remained unrepaired 24 h after ex vivo incubation. Isoproterenol-induced DNA strand breaks could be partially prevented by pre-treatment with the beta-adrenergic receptor antagonist propranolol. Furthermore, the level of PARP-1 protein and PARP activity decreased and the levels of the PARP substrate nicotinamide adenine dinucleotide (NAD(+)) and of adenosine triphosphate (ATP), necessary to replenish NAD(+) pools, were lowered by isoproterenol treatment. In conclusion our data provide novel insights into the mechanisms of isoproterenol-induced genotoxicity linking beta-adrenergic stimulation and PARP-1.
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