Doxorubicin Inhibits Cardiomyocyte Autophagic Flux by Suppressing Lysosomal Acidification
| dc.contributor.advisor | Sadek, Hesham A. | en |
| dc.contributor.committeeMember | Hill, Joseph A. | en |
| dc.contributor.committeeMember | Levine, Beth | en |
| dc.contributor.committeeMember | Amatruda, James F. | en |
| dc.creator | Li, Dan | en |
| dc.date.accessioned | 2017-06-02T15:28:21Z | |
| dc.date.available | 2017-06-02T15:28:21Z | |
| dc.date.created | 2015-05 | |
| dc.date.issued | 2015-04-09 | |
| dc.date.submitted | May 2015 | |
| dc.date.updated | 2017-06-02T15:15:08Z | |
| dc.description.abstract | The 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.mimetype | application/pdf | en |
| dc.identifier.oclc | 988778282 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/4128 | |
| dc.language.iso | en | en |
| dc.subject | Antibiotics, Antineoplastic | en |
| dc.subject | Autophagy | en |
| dc.subject | Doxorubicin | en |
| dc.subject | Lysosomes | en |
| dc.subject | Myocytes, Cardiac | en |
| dc.title | Doxorubicin Inhibits Cardiomyocyte Autophagic Flux by Suppressing Lysosomal Acidification | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Genetics and Development | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |