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Updated: Mar 24, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification
Dan L Li1, Zhao V Wang1, Guanqiao Ding1
1From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX.
Background:
The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined.
Methods And Results:
Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response.
Conclusions:
Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.
Insights
Doxorubicin hinders autophagy in heart cells by blocking lysosome function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity, offering a potential therapeutic strategy for heart damage.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Pharmacology
Background:
- Doxorubicin chemotherapy is limited by cardiotoxicity, characterized by myocardial fibrosis and vacuolated cardiomyocytes.
- The role of autophagy in doxorubicin-induced heart damage is not well understood.
- Existing models of cardiotoxicity confound autophagy interpretation due to severe systemic effects.
Purpose of the Study:
- To investigate the role of autophagy in doxorubicin cardiotoxicity.
- To establish a refined model of doxorubicin cardiotoxicity for clearer autophagy analysis.
- To identify the specific mechanism by which doxorubicin affects autophagy in cardiomyocytes.
Main Methods:
- Developed a novel model of modest, progressive cardiotoxicity without constitutional symptoms.
- Assessed autophagic flux in cardiomyocytes in vivo and in culture using doxorubicin.
- Examined lysosomal acidification and function.
- Utilized Beclin 1 haploinsufficient and overexpressing mice to study autophagy's functional relevance.
Main Results:
- Doxorubicin was found to block autophagic flux in cardiomyocytes, leading to autolysosome accumulation.
- The block was attributed to impaired lysosome acidification.
- Mice with reduced autophagy (Beclin 1+/-) were protected from doxorubicin cardiotoxicity.
- Mice overexpressing Beclin 1 showed exacerbated cardiotoxicity.
Conclusions:
- Doxorubicin impairs cardiomyocyte autophagy by inhibiting lysosome acidification and function.
- Decreasing autophagy initiation provides protection against doxorubicin-induced cardiotoxicity.
- Targeting autophagy modulation may be a strategy to mitigate doxorubicin's harmful effects on the heart.
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