title: Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.
abstract: 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.
  
  
  
  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.
  
  
  
  Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.
authors.affiliation: From 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.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Li
authors.affiliation: From 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.
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.affiliation: From 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.
authors.forename: Guanqiao
authors.initials: G
authors.lastname: Ding
authors.affiliation: From 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: From 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.
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.affiliation: From 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.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.affiliation: From 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.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: From 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.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: From 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.
authors.forename: Herman
authors.initials: H
authors.lastname: May
authors.affiliation: From 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.
authors.forename: Viktoriia
authors.initials: V
authors.lastname: Kyrychenko
authors.affiliation: From 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.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Schneider
authors.affiliation: From 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.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gillette
authors.affiliation: From 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. joseph.hill@utsouthwestern.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin
keywords: autophagy; cardiotoxicity; doxorubicin; drug therapy; myocytes, cardiac