PO-251 Modulation of NAD+levels by NQO1 enzymatic action alleviates adriamycin-induced cardiac dysfunction in mice

Abstract

IntroductionAdriamycin (ADR) is a potent anticancer drug widely used to treat a variety of human neoplasms. Nevertheless, its clinical application is hampered because of severe side effects such as cardiotoxicity and heart failure. ADR-induced cardiomyopathy (AIC) has been reported to be caused by myocardial damage and dysfunction through oxidative stress, DNA damage, and inflammatory responses. But, the remedy for ADR cardiomyopathy is still not developed. We describe the effect of NAD+/NADH modulation by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action on AIC.Material and methodsAIC was established by three times intraperitoneal injections of ADR (cumulative dose of 12 mg/kg i.p.; 4 mg/kg every day for 3 consecutive days) in C57BL/6 wild-type (WT) and NQO1 knockout (NQO1-/-) mice. Before and after exposure to ADR, the mice were orally administered dunnione (20 mg/kg), a substrate of NQO1. Cardiac biomarker levels in the plasma, cardiac dysfunction, oxidative biomarkers, and mRNA and protein levels of pro-inflammatory mediators were determined to compare the cardiac toxicity of each experimental group.Results and discussionsAll biomarkers of Cardiac damage and oxidative stress, and mRNA levels of pro-inflammatory cytokines, including cardiac dysfunction were significantly increased in ADR-treated both WT and NQO1-/- mice. However, this increase was significantly reduced by dunnione in WT, but not in NQO1-/- mice. In addition, a decrease in SIRT1 activity due to a decrease in the NAD+/NADH ratio by PARP-1 hyperactivation was associated with ADR-induced cardiotoxicity through increased nuclear factor (NF)-κB p65 and p53 acetylation in both WT and NQO1-/- mice, whereas an increase in NAD+/NADH ratio by NQO1 enzymatic action using dunnione as a substrate recovered SIRT1 activity and subsequently deacetylated NF-κB p65 and p53 in WT, however not in NQO1-/- mice thereby attenuating AIC.ConclusionDunnione has a cardioprotective effect against ADR-induced cardiomyopathy through NQO1 enzymatic action. Thus, modulation of NAD+/NADH by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated heart failure, including AIC.