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https://hdl.handle.net/10316/88473
Title: | Doxorubicin persistently rewires cardiac circadian homeostasis in mice | Authors: | Ferreira, Luciana L Cervantes, Marlene Froufe, Hugo J. C. Egas, Conceição Cunha-Oliveira, Teresa Sassone-Corsi, Paolo Oliveira, Paulo J. |
Keywords: | Cardiotoxicity; Chemotherapy; Circadian clock; Doxorubicin; Mitochondria; Protein acetylation | Issue Date: | 25-Nov-2019 | Serial title, monograph or event: | Archives of Toxicology | Abstract: | Circadian rhythms disruption can be the cause of chronic diseases. External cues, including therapeutic drugs, have been shown to modulate peripheral-circadian clocks. Since anthracycline cardiotoxicity is associated with loss of mitochondrial function and metabolic remodeling, we investigated whether the energetic failure induced by sub-chronic doxorubicin (DOX) treatment in juvenile mice was associated with persistent disruption of circadian regulators. Juvenile C57BL/6J male mice were subjected to a sub-chronic DOX treatment (4 weekly injections of 5 mg/kg DOX) and several cardiac parameters, as well as circadian-gene expression and acetylation patterns, were analyzed after 6 weeks of recovery time. Complementary experiments were performed with Mouse Embryonic Fibroblasts (MEFs) and Human Embryonic Kidney 293 cells. DOX-treated juvenile mice showed cardiotoxicity markers and persistent alterations of transcriptional- and signaling cardiac circadian homeostasis. The results showed a delayed influence of DOX on gene expression, accompanied by changes in SIRT1-mediated cyclic deacetylation. The mechanism behind DOX interference with the circadian clock was further studied in vitro, in which were observed alterations of circadian-gene expression and increased BMAL1 SIRT1-mediated deacetylation. In conclusion, DOX treatment in juvenile mice resulted in disruption of oscillatory molecular mechanisms including gene expression and acetylation profiles. | URI: | https://hdl.handle.net/10316/88473 | ISSN: | 0340-5761 1432-0738 |
DOI: | 10.1007/s00204-019-02626-z | Rights: | embargoedAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
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