Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

Dan L. Li, Zhao Wang, Guanqiao Ding, Wei Tan, Xiang Luo, Alfredo Criollo, Min Xie, Nan Jiang, Herman May, Viktoriia Kyrychenko, Jay W Schneider, Thomas G. Gillette, Joseph A Hill

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1668-1687
Number of pages20
JournalCirculation
Volume133
Issue number17
DOIs
StatePublished - Apr 26 2016

Keywords

  • autophagy
  • cardiotoxicity
  • doxorubicin
  • drug therapy
  • myocytes, cardiac

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Li, D. L., Wang, Z., Ding, G., Tan, W., Luo, X., Criollo, A., Xie, M., Jiang, N., May, H., Kyrychenko, V., Schneider, J. W., Gillette, T. G., & Hill, J. A. (2016). Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification. Circulation, 133(17), 1668-1687. https://doi.org/10.1161/CIRCULATIONAHA.115.017443