title: Accelerated aging during chronic oxidative stress: a role for PARP-1.
abstract: Oxidative stress plays a major role in the pathophysiology of chronic inflammatory disease and it has also been linked to accelerated telomere shortening. Telomeres are specialized structures at the ends of linear chromosomes that protect these ends from degradation and fusion. Telomeres shorten with each cell division eventually leading to cellular senescence. Research has shown that poly(ADP-ribose) polymerase-1 (PARP-1) and subtelomeric methylation play a role in telomere stability. We hypothesized that PARP-1 plays a role in accelerated aging in chronic inflammatory diseases due to its role as coactivator of NF-κb and AP-1. Therefore we evaluated the effect of chronic PARP-1 inhibition (by fisetin and minocycline) in human fibroblasts (HF) cultured under normal conditions and under conditions of chronic oxidative stress, induced by tert-butyl hydroperoxide (t-BHP). Results showed that PARP-1 inhibition under normal culturing conditions accelerated the rate of telomere shortening. However, under conditions of chronic oxidative stress, PARP-1 inhibition did not show accelerated telomere shortening. We also observed a strong correlation between telomere length and subtelomeric methylation status of HF cells. We conclude that chronic PARP-1 inhibition appears to be beneficial in conditions of chronic oxidative stress but may be detrimental under relatively normal conditions.
authors: Department of Toxicology, Maastricht University, P.O. Box 6200 MD, Maastricht, The Netherlands.
authors: Daniëlle M P H J
authors: DM
authors: Boesten
authors: Joyce M J
authors: JM
authors: de Vos-Houben
authors: Leen
authors: L
authors: Timmermans
authors: Gertjan J M
authors: GJ
authors: den Hartog
authors: Aalt
authors: A
authors: Bast
authors: Geja J
authors: GJ
authors: Hageman
mesh_terms: D016922:Cellular Senescence / Q000187:drug effects; D002889:Chromosomes, Human, Pair 2 / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D044948:Flavonols; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008911:Minocycline / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D059505:Telomere Homeostasis / Q000187:drug effects; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D005419:Flavonoids; D044948:Flavonols; D011064:Poly Adenosine Diphosphate Ribose; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019098:Telomerase; D008911:Minocycline; C017875:fisetin