{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/4128"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/4128","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Doxorubicin Inhibits Cardiomyocyte Autophagic Flux by Suppressing Lysosomal Acidification","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Li, Dan"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Sadek, Hesham A.","Hill, Joseph A.","Levine, Beth","Amatruda, James F."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-06-02T15:28:21Z","date_published":"2017-06-02T15:28:21Z","updated_at":"2026-07-24T05:52:22Z","subjects":["Antibiotics, Antineoplastic","Autophagy","Doxorubicin","Lysosomes","Myocytes, Cardiac"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["988778282"],"render_values":[{"text":"988778282","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/4128","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Sadek, Hesham A.","Hill, Joseph A.","Levine, Beth","Amatruda, James F."]},{"key":"dc:creator","label":"Author","values":["Li, Dan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2017-06-02T15:28:21Z","2015-05","2015-04-09","May 2015","2017-06-02T15:15:08Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Antibiotics, Antineoplastic","Autophagy","Doxorubicin","Lysosomes","Myocytes, Cardiac"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/4128","988778282"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Doxorubicin Inhibits Cardiomyocyte Autophagic Flux by Suppressing Lysosomal Acidification"]}]}],"canonical_facts":{"dc:contributor":["Sadek, Hesham A.","Hill, Joseph A.","Levine, Beth","Amatruda, James F."],"dc:creator":["Li, Dan"],"dc:date":["2017-06-02T15:28:21Z","2015-05","2015-04-09","May 2015","2017-06-02T15:15:08Z"],"dc:description":["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."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/4128","988778282"],"dc:language":["en"],"dc:subject":["Antibiotics, Antineoplastic","Autophagy","Doxorubicin","Lysosomes","Myocytes, Cardiac"],"dc:title":["Doxorubicin Inhibits Cardiomyocyte Autophagic Flux by Suppressing Lysosomal Acidification"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:22Z"}