Abstract
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. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency 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 deficiency 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 deficiency 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.
Highlights
Doxorubicin (DOX) is an effective chemotherapeutic agent in the treatment of a broad range of human solid and hematogenous malignancies
Ultraviolet irradiation resistance-associated gene (UVRAG)-deficient mice developed more pronounced fibrosis 5 days after DOX treatment (Fig. 1d,e). In agreement with these findings, the expression of α-smooth muscle actin (α-SMA), a marker of active cardiac fibroblast[25], was enhanced in left ventricles (LVs) from DOX-treated UVRAG-deficient mice compared with wild type (WT) controls (Fig. S2a,b)
The survival rate was significantly lower in UVRAG-deficient mice compared with WT controls after DOX treatment
Summary
Doxorubicin (DOX) is an effective chemotherapeutic agent in the treatment of a broad range of human solid and hematogenous malignancies. DOX-induced cardiotoxicity can be acute and chronic. Modulation of any step of autophagy process can alter autophagic flux. Whether cardiac autophagy is activated or impaired and which specific step is modulated in DOX-induced carditoxicity is not completely understood. Ultraviolet irradiation resistance-associated gene (UVRAG), an autophagy-related protein, has been shown to regulate autophagosome formation[20], maturation[21] and autophagic lysosomal reformation (ALR)[22]. We have recently obtained a line of UVRAG-deficient mice screened by piggyBac transposition and demonstrated that UVRAG deficiency leads to impaired autophagic flux accompanied with accumulated autophagosomes in the heart, suggesting that UVRAG regulates autophagosome maturation of cardiac autophagy[23,24]. UVRAG deficiency aggravates DOX-induced impaired autophagic flux in the heart. We provide evidence that intermittent fasting rescues impaired autophagy and ameliorates pathological alterations in DOX cardiotoxicity
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