42 Identification of an inherent mechanism of NADPH oxidase signalling in doxorubicin cardiotoxicity

Anthracyclines used in cancer therapeutics, including doxorubicin (DOX), cause both short- and long-term cardiotoxicity associated with increased myocardial oxidative stress. Chronic DOX treatment increases superoxide anion production in vivo, which is derived largely from Nox2 NADPH oxidase and contributes to key processes underlying cardiac dysfunction. The aim of this study was to identify possible mechanisms involved in the signal relay from increased Nox2 activity to development of disease phenotype. In this context, we performed a whole-genome gene expression array (Illumina MouseWG-6 v2.0) of ventricular tissue from DOX-treated wild type vs Nox2KO mice. Pathway analysis (GeneGo Metacore) revealed the apoptotic process most significant to the data set (p=0.00005). Applying the 63 relevant genes (FDR cut-off, adjusted p