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dc.contributor.advisorSadek, Hesham A.en
dc.creatorLi, Danen
dc.date.accessioned2017-06-02T15:28:21Z
dc.date.available2017-06-02T15:28:21Z
dc.date.created2015-05
dc.date.issued2015-04-09
dc.date.submittedMay 2015
dc.identifier.urihttp://hdl.handle.net/2152.5/4128
dc.description.abstractThe clinical use of doxorubicin is limited by cardiotoxicity. Dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases. However, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Most models of acute 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, I first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, and is reminiscent of the effects seen in patients of chronic doxorubicin cardiomyopathy. Next, via multiple assays I showed that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. Moreover, I went on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, I studied animals with diminished autophagic activity due to haploinsufficiency for Beclin 1. Beclin 1+/- mice exposed to doxorubicin manifested restored cardiac autophagic flux, and were protected in terms of structural and functional changes within the myocardium. Conversely, animals over-expressing Beclin 1 manifested an amplified cardiotoxic response, correlating with their aggravated accumulation of autolysosomes in cardiomyocytes after doxorubicin treatments. In summary, I report here that doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Further, reducing autophagy initiation may protect against doxorubicin cardiotoxicity.en
dc.format.mimetypeapplication/pdfen
dc.language.isoenen
dc.subjectAntibiotics, Antineoplasticen
dc.subjectAutophagyen
dc.subjectDoxorubicinen
dc.subjectLysosomesen
dc.subjectMyocytes, Cardiacen
dc.titleDoxorubicin Inhibits Cardiomyocyte Autophagic Flux by Suppressing Lysosomal Acidificationen
dc.typeThesisen
dc.date.updated2017-06-02T15:15:08Z
dc.type.materialtexten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.nameDoctor of Philosophyen
thesis.degree.levelDoctoralen
thesis.degree.disciplineGenetics and Developmenten
dc.contributor.committeeMemberHill, Joseph A.en
dc.contributor.committeeMemberLevine, Bethen
dc.contributor.committeeMemberAmatruda, James F.en
dc.identifier.oclc988778282


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