UVRAG Deficiency Exacerbates Doxorubicin-induced Cardiotoxicity

Doxorubicin(DOX)is an effective chemotherapeutic drug in the treatment of various types of cancers.However,its clinical application has been largely limited by potential development of cardiotoxicity.Previously we have shown that ultra-violet radiation resistance-associated gene(UVRAG),an autophagy-related protein,is essential for the maintenance of autophagic flux in the heart under physiological conditions.UVRAG-deficient mice at 2 and 6 months of age showed normal cardiac structure and function.However,by 10 months of age,UVRAG-deficient mice developed age-related dilated cardiomyopathy.In this study,we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity.Acute or chronic DOX-induced cardiotoxicity in wild type(WT)and UVRAG-deficient mice were established by a single intraperitoneal injection of DOX(20 mg/kg)or intraperitoneal injection of 6 doses of DOX(4 mg/kg/week)at weekly intervals,respectively.UVRAG defciency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization,enhanced collagen accumulation,elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase,higher ROS levels,aggravated apoptosis and more depressed cardiac function.Autophagic flux was impaired in DOX-induced cardiotoxicity.UVRAG defciency aggravated impaired autophagic flux in DOX-induced cardiotoxicity.Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity.Collectively,our data suggest that UVRAG defciency exacerbates DOX-induced cardiotoxicity,at least in part,through aggravation of DOX-induced impaired autophagic flux.Intermittent fasting,which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity,may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity.