title: Poly(ADP-ribose) polymerase-2 depletion reduces doxorubicin-induced damage through SIRT1 induction.
abstract: OBJECTIVE
  Doxorubicin (DOX) is widely used in cytostatic treatments, although it may cause cardiovascular dysfunction as a side effect. DOX treatment leads to enhanced free radical production that in turn causes DNA strand breakage culminating in poly(ADP-ribose) polymerase (PARP) activation and mitochondrial and cellular dysfunction. DNA nicks can activate numerous enzymes, such as PARP-2. Depletion of PARP-2 has been shown to result in a protective phenotype against free radical-mediated diseases, suggesting similar properties in the case of DOX-induced vascular damage.
  
  
  RESULTS
  PARP-2(+/+) and PARP-2(-/-) mice and aortic smooth muscle (MOVAS) cells were treated with DOX (25 mg/kg or 3 μM, respectively). Aortas were harvested 2-day post-treatment while MOVAS cells were treated with DOX for 7 hours. Aortas from PARP-2(-/-) mice displayed partial protection against DOX toxicity, and the protection depended on the conservation of smooth muscle but not on the conservation of endothelial function. DOX treatment evoked free radical production, DNA breakage and PARP activation. Importantly, depletion of PARP-2 did not quench any of these phenomena, suggesting an alternative mechanism. Depletion of PARP-2 prevented DOX-induced mitochondrial dysfunction through SIRT1 activation. Genetic deletion of PARP-2 resulted in the induction of the SIRT1 promoter and consequently increased SIRT1 expression both in aortas and in MOVAS cells. SIRT1 activation enhanced mitochondrial biogenesis, which provided protection against DOX-induced mitochondrial damage.
  
  
  CONCLUSIONS
  Our data identify PARP-2 as a mediator of DOX toxicity by regulating vascular SIRT1 activity and mitochondrial biogenesis. Moreover, to the best of our knowledge, this is the first report of SIRT1 as a protective factor in the vasculature upon oxidative stress.
authors.affiliation: Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Nagyerdei krt 98. Pf. 7, H-4032 Debrecen, Hungary.
authors.forename: Magdolna
authors.initials: M
authors.lastname: Szántó
authors.forename: Ibolya
authors.initials: I
authors.lastname: Rutkai
authors.forename: Csaba
authors.initials: C
authors.lastname: Hegedus
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Czikora
authors.forename: Máté
authors.initials: M
authors.lastname: Rózsahegyi
authors.forename: Borbála
authors.initials: B
authors.lastname: Kiss
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Pál
authors.initials: P
authors.lastname: Gergely
authors.forename: Attila
authors.initials: A
authors.lastname: Tóth
authors.forename: Péter
authors.initials: P
authors.lastname: Bai
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D019610:Cytoprotection; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1