Abstract 12522: Preceding Starvation Prevents Acute Doxorubicin Cardiotoxicity via Autophagy Activation
Doxorubicin is a highly effective antineoplastic drug, but its clinical use is limited by the adverse effects on the heart. Active autophagy has recently been reported in doxorubicin cardiotoxicity but its pathophysiological role remains unclear. In the present study, we examined effect of preceding starvation, a potent inducer of autophagy, on doxorubicin cardiotoxicity. Cardiotoxicity was induced in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice by injection of 10 mg/kg doxorubicin twice per week. The experimental group was deprived of food for 48 h before each injection of doxorubicin to induce autophagy. Doxorubicin treatment caused left ventricular dilatation and dysfunction at 1 week after the initial injection (the left ventricular diameter [LVDd] = 3.94±0.25 mm and ejection fraction [EF] = 46.7±4.4%), which were significantly mitigated by the preceding starvation (LEDd = 3.41±0.31 mm and EF = 63.9±6.4%, both p < 0.05 compared with the control). Cardiomyocyte autophagy appeared markedly activated in the doxorubicin-treated group according to assessment of LC3 by immunohistochemistry and Western blotting. According to LC3 expression, autophagy appeared to be rather attenuated by the preceding starvation. Unexpectedly, however, myocardial ATP content was decreased in the doxorubicin-treated group and this reduction was restored by the preceding starvation. Electron microscopy suggested that autophagic process is indeed initiated but not completed in the doxorubicin-treated group, i.e., autophagosome digestion is insufficient, and that this incompletion was partially improved by starvation. Finally autophagy flux assay using chloroquine confirmed that doxorubicin impairs final digestion step of autophagy in cardiomyocytes. In conclusion, preceding starvation mitigates acute doxorubicin cardiotoxicity, of which underlying mechanism may be, at least in part, restoration of autophagy flux which is impaired by doxorubicin. Our findings imply that fasting could be a possible strategy for preventing doxorubicin cardiotoxicity.
- © 2011 by American Heart Association, Inc.