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Poly(ADP-ribose) polymerase-2 depletion reduces doxorubicin-induced damage through SIRT1 induction.
Cardiovasc Res. 2011 Dec 01; 92(3):430-8.CR

Abstract

AIMS

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.

METHODS AND 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.

CONCLUSION

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+Show Affiliations

Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Nagyerdei krt 98. Pf. 7, H-4032 Debrecen, Hungary.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21921080

Citation

Szántó, Magdolna, et al. "Poly(ADP-ribose) Polymerase-2 Depletion Reduces Doxorubicin-induced Damage Through SIRT1 Induction." Cardiovascular Research, vol. 92, no. 3, 2011, pp. 430-8.
Szántó M, Rutkai I, Hegedus C, et al. Poly(ADP-ribose) polymerase-2 depletion reduces doxorubicin-induced damage through SIRT1 induction. Cardiovasc Res. 2011;92(3):430-8.
Szántó, M., Rutkai, I., Hegedus, C., Czikora, Á., Rózsahegyi, M., Kiss, B., Virág, L., Gergely, P., Tóth, A., & Bai, P. (2011). Poly(ADP-ribose) polymerase-2 depletion reduces doxorubicin-induced damage through SIRT1 induction. Cardiovascular Research, 92(3), 430-8. https://doi.org/10.1093/cvr/cvr246
Szántó M, et al. Poly(ADP-ribose) Polymerase-2 Depletion Reduces Doxorubicin-induced Damage Through SIRT1 Induction. Cardiovasc Res. 2011 Dec 1;92(3):430-8. PubMed PMID: 21921080.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Poly(ADP-ribose) polymerase-2 depletion reduces doxorubicin-induced damage through SIRT1 induction. AU - Szántó,Magdolna, AU - Rutkai,Ibolya, AU - Hegedus,Csaba, AU - Czikora,Ágnes, AU - Rózsahegyi,Máté, AU - Kiss,Borbála, AU - Virág,László, AU - Gergely,Pál, AU - Tóth,Attila, AU - Bai,Péter, Y1 - 2011/09/15/ PY - 2011/9/17/entrez PY - 2011/9/17/pubmed PY - 2012/3/3/medline SP - 430 EP - 8 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 92 IS - 3 N2 - AIMS: 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. METHODS AND 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. CONCLUSION: 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/21921080/Poly_ADP_ribose__polymerase_2_depletion_reduces_doxorubicin_induced_damage_through_SIRT1_induction_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvr246 DB - PRIME DP - Unbound Medicine ER -