P53 inhibition exacerbates late-stage anthracycline cardiotoxicity

dc.contributor.authorZhu, Wuqiang
dc.contributor.authorZhang, Wenjun
dc.contributor.authorShou, Weinian
dc.contributor.authorField, Lauren J.
dc.contributor.departmentDepartment of Pediatrics, IU School of Medicineen_US
dc.date.accessioned2016-03-16T16:39:20Z
dc.date.available2016-03-16T16:39:20Z
dc.date.issued2014-07-01
dc.description.abstractAIMS: Doxorubicin (DOX) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model. METHODS AND RESULTS: Two-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals. CONCLUSION: These data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment.en_US
dc.identifier.citationZhu, W., Zhang, W., Shou, W., & Field, L. J. (2014). P53 inhibition exacerbates late-stage anthracycline cardiotoxicity. Cardiovascular Research, 103(1), 81–89. http://doi.org/10.1093/cvr/cvu118en_US
dc.identifier.urihttps://hdl.handle.net/1805/8877
dc.language.isoen_USen_US
dc.publisherOxford University Pressen_US
dc.relation.isversionof10.1093/cvr/cvu118en_US
dc.relation.journalCardiovascular Researchen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectApoptosisen_US
dc.subjectHeart failureen_US
dc.subjectMyocytesen_US
dc.titleP53 inhibition exacerbates late-stage anthracycline cardiotoxicityen_US
dc.typeArticleen_US
ul.alternative.fulltexthttp://pubmed.gov/24812279en_US
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