Abstract 13288: Doxorubicin Induces Cardiotoxicity by Inhibiting Autophagic Flux in Cardiomyocytes
Introduction: Doxorubicin, a potent chemotherapeutic agent widely used in oncological practice is notorious for its cardiotoxic side effects. However, mechanisms underlying doxorubicin-induced cardiomyopathy remain largely unknown. Autophagy, an evolutionarily conserved catabolic process, plays important roles in cardiac physiology and pathophysiology. Here, we tested the hypothesis that doxorubicin suppresses autophagic flux in cardiomyocytes, thereby promoting cardiomyopathy.
Methods: First, we developed an in vivo model of doxorubicin-induced cardiotoxicity that closely mimics events seen in humans (modest declines in contractile performance, absence of constitutional symptoms). Autophagy was assessed by measuring LC3-II levels and autophagic puncta formation, and flux was probed using Bafilomycin A1 (BFA). To evaluate the role of autophagic flux in the pathogenesis of doxorubicin-elicited cardiomyopathy, we also studied mice haploinsufficient for Beclin 1 (a molecule involved in both early and late events in the autophagic cascade) and cardiomyocyte-specific Beclin 1 transgenic (αMHC-Beclin 1) mice.
Results: Doxorubicin suppressed basal autophagic flux, as well as rapamycin- and starvation-induced autophagic flux, in both neonatal rat ventricular myocytes (NRVMs) and in hearts. Beclin 1+/- mice were protected from doxorubicin-induced cardiomyopathy: % fractional shortening (%FS) by echocardiography: vehicle WT 61.2%, vehicle Beclin 1+/- 60.4%; doxorubicin WT 51.4%, doxorubicin Beclin 1+/- 58.3% (p<0.05, n=7 in each group). Conversely, αMHC-Beclin 1 transgenic mice exposed to doxorubicin manifested enhanced pathological changes: %FS: vehicle WT 61.3%, vehicle αMHC-Beclin 1 62.0%, doxorubicin WT 51.1%, doxorubicin αMHC-Beclin 1 45.7% (p<0.05, n=6 in each group).
Conclusions: In a model of doxorubicin toxicity that is not marked by systemic effects (anorexia, lethargy, weight loss) which confound analysis of autophagy, doxorubicin suppresses cardiomyocyte autophagic flux. Genetic titration of the autophagic response by means of Beclin 1 loss- and gain-of-function manipulations implicates doxorubicin-induced alterations in cardiomyocyte autophagy in this biology.
- © 2013 by American Heart Association, Inc.