Abstract 20228: Nicotinamide Riboside Improves Autophagic Flux and Prevents Doxorubicin-Induced Cardiac Injury

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Introduction: Doxorubicin is widely used as a first-line chemotherapeutic drug for various malignancies. However, doxorubicin causes severe cardiotoxicity. Recent studies report that autophagic flux is impaired and contributes to doxorubicin-induced cardiac injury. Nicotinamide riboside (NR) is a precursor of NAD+, a co-factor required for Sirt1 activity. Activation of Sirt1 improves autophagic flux. However, the effects of NR have never been reported in doxorubicin-induced cardiac injury.

Hypothesis: NR prevents doxorubicin-induced cardiac injury through Sirt1-mediated improvement of autophagic flux.

Methods: Cardiac injury was induced in mice by injection of doxorubicin (20 mg/kg, i.p.). NR (300 mg/kg, i.p.) was given 30 min before doxorubicin injection. Myocardial function was assessed by echocardiography 5 days after doxorubicin injection. Cultured cardiomyocytes were incubated with NR followed by doxorubicin (1 μmol/L) for 24 hours. Apoptosis, autophagy and reactive oxygen species (ROS) were analyzed.

Results: Administration of NR elevated NAD+ levels, reduced ROS production, inhibited apoptosis and improved autophagic flux, lending to an attenuation of myocardial dysfunction in doxorubicin-injected mice. These protective effects of NR were offset by inhibition of Sirt1 activity with EX-527 and inhibition of autophagic flux with chloroquine. In cultured cardiomyocytes, NR improved autophagic flux, prevented apoptosis and inhibited ROS production induced by doxorubicin. Consistently, incubation with EX527 and chloroquine abrogated these inhibitory effects of NR in doxorubicin-induced cardiomyocytes. In contrast, incubation with NR did not affect doxorubicin-induced apoptosis in tumor cells.

Conclusions: NR prevents doxorubicin-induced cardiac injury by boosting NAD+/Sirt1 signaling and improving autophagic flux. Thus, NR may be a potentially useful drug to prevent doxorubicin-induced cardiotoxicity.

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