Nicotinamide Riboside Protects Against Doxorubicin-induced Cardiotoxicity By Improving Autophagic Flux

IntroductionDoxorubicin is widely used as a first-line chemotherapeutic drug for various malignancies.However,doxorubicin causes severe cardiotoxicity and effective therapies are limited.Recent studies showed that impaired autophagic flux contributes to doxorubicin-induced cardiac injury.Nicotinamide riboside(NR)is a precursor of NAD+,which has been implicated in various patho-physiological processes.This study aimed to investigate whether NR protects against doxorubicin-induced cardiotoxicity by improving autophagic flux.MethodsCardiac injury was induced in mice by injection of doxorubicin(20 mg/kg,i.p.).NR(100-500 mg/kg,i.p.)was given 30 min before doxorubicin injection.Myocardial function was assessed by echocardiography and myocardial injury analyzed 5 days after doxorubicin injection.Cultured cardiomyocytes were incubated with NR followed by doxorubicin(1 μmol/L)for 24 hours.Apoptosis,necroptosis and oxidant stress were determined.Autophagy and autophagic flux were analyzed in cardiomyocytes in vitro and mice in vivo.ResultsAdministration of NR reduced oxidant stress,inhibited cardiac cell death and attenuated myocardial dysfunction in doxorubicin-injected mice in a dose-dependent manner.NR also prevented autophagic flux block in doxorubicin-injected mouse hearts.These protective effects of NR were associated with improved autophagic flux and offset by inhibition of autophagic flux with chloroquine or by inhibition of Sirt1 activity with EX-527.In cultured cardiomyocytes,NR improved autophagic flux,inhibited oxidant stress,and prevented apoptosis and necroptosis induced by doxorubicin.Consistently,chloroquine and EX-527 abrogated these protective effects of NR in doxorubicin-induced cardiomyocytes.ConclusionsNR prevents doxorubicin-induced cardiac injury by improving autophagic flux via the NAD+/Sirt1 signaling.Thus,NR may be a potentially useful drug to prevent doxorubicin-induced cardiotoxicity.