POLY(ADP‐RIBOSE) POLYMERASE‐2 DEPLETION REDUCES DOXORUBICIN‐INDUCED DAMAGE THROUGH SIRT1 INDUCTION

Abstract

Doxorubicin (DOX) is used in cytostatic treatments, although it may cause cardiovascular dysfunction. DOX treatment leads to enhanced free radical production that in turn cause DNA strand breakage culminating in poly(ADP‐ribose) polymerase (PARP) activation, mitochondrial and cellular dysfunction. DNA nicks can activate the PARP‐2 enzyme. 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. PARP‐2(+/+) and (−/−) mice and aortic smooth muscle (MOVAS) cells were treated with DOX (25 mg/kg, or 3 μM, respectively). Aortae from PARP‐2(−/−) mice displayed partial protection against DOX toxicity. Depletion of PARP‐2 prevented DOX‐induced mitochondrial dysfunction through SIRT1 activation. Genetic deletion of PARP‐2 resulted in the induction of SIRT1 promoter and consequently increased SIRT1 expression both in aortae and in MOVAS cells. SIRT1 activation enhanced mitochondrial biogenesis. Our data identify PARP‐2 as a mediator of DOX toxicity by regulating vascular SIRT1 activity and mitochondrial biogenesis. Moreover, to our best knowledge this is the first report of SIRT1 as a protective factor in the vasculature upon oxidative stress. This work was supported by TÁMOP 4.2.1./B‐09/1/KONV‐2010‐0007 and 4.2.2‐08/1‐2008‐0019.