UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

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.

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…Furthermore, the authors studies tissue-specific loss-of-function models of ATG7, a protein critical for autophagosome formation, and demonstrate the critical need for autophagy signaling in individual tissues for the specific benefits. Intermittent fasting has also been demonstrated to prevent doxorubicin-induced cardiomyopathy in a mouse model of repetitive doxycycline exposure resulting in cardiomyopathy (7). Intermittent fasting rescued the impaired autophagic flux in this setting, which was worsened by concomitant deficiency of UVRAG, a protein essential for autophagosome formation.…”

Cardioprotective Effects of Intermittent Fasting

“…We and others have recently shown that autophagic flux is impaired in the mouse models of doxorubicin-induced cardiotoxicity, which contributes to heart injury [14][15][16]. Moreover, we have shown that IF is capable of restoring autophagic flux and ameliorating pathological alterations including increased cytoplasmic vacuolization, fibrosis, apoptosis and generation of reactive oxygen species in both acute and chronic doxorubicin cardiotoxicity [16]. Thus, IF could serve as a promising strategy for the prevention and control of doxorubicininduced cardiotoxicity.…”

Doxorubicin-Induced Cardiotoxicity

“…The discrepancies may be caused by the difference in animal species, cell types, methods monitoring autophagy, means of drug administration, and dosage and duration of the drug used in these studies. More recently, we and others have shown that DOX treatment stimulated autophagy initiation, while suppressed multiple subsequent steps including autophagosome formation, autophagosome maturation and lysosomal degradation [7,27,29,30]. As a consequence, the autophagic flux was attenuated in DOX-induced cardiotoxicity.…”

“…However, it is controversial whether autophagy is activated or suppressed. There are studies showing that DOX treatment activates autophagy in the heart or cardiomyocytes [23][24][25][26], while others have shown conflicting results [7,[27][28][29][30]. Moreover, the significance of autophagy in DOX cardiotoxicity is still on debate.…”

“…Moreover, the significance of autophagy in DOX cardiotoxicity is still on debate. Some data are in favor of beneficial effects of autophagy in DOX cardiotoxicity [23][24][25][26], while others argue against it [27][28][29][30]. The discrepancies may be caused by the difference in animal species, cell types, methods monitoring autophagy, means of drug administration, and dosage and duration of the drug used in these studies.…”