Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy.
Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threaten...
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180571&type=printable |
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| author | Izabela Piotrowska Mark Isalan Michal Mielcarek |
| author_facet | Izabela Piotrowska Mark Isalan Michal Mielcarek |
| author_sort | Izabela Piotrowska |
| collection | DOAJ |
| description | Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects. Hence, a number of studies have defined a "safe dose" of the drug, both in animal models and clinical settings, with the aim of avoiding long-term cardiac effects. Here we show that a dose generally considered as safe in a mouse model can induce harmful changes in the myocardium, as early as 2 weeks after infusion. The adverse changes include the development of fibrotic lesions, disarray of cardiomyocytes and a major transcription dysregulation. Importantly, low-dose doxorubicin caused specific changes in the transcriptional profile of several histone deacetylases (HDACs) which are epigenetic regulators of cardiac remodelling. This suggests that cardioprotective therapies, aimed at modulating HDACs during doxorubicin treatment, deserve further exploration. |
| format | Article |
| id | doaj-art-0701e17d3499440192adbe8e5ccfad56 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-0701e17d3499440192adbe8e5ccfad562025-08-20T03:07:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01126e018057110.1371/journal.pone.0180571Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy.Izabela PiotrowskaMark IsalanMichal MielcarekDoxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects. Hence, a number of studies have defined a "safe dose" of the drug, both in animal models and clinical settings, with the aim of avoiding long-term cardiac effects. Here we show that a dose generally considered as safe in a mouse model can induce harmful changes in the myocardium, as early as 2 weeks after infusion. The adverse changes include the development of fibrotic lesions, disarray of cardiomyocytes and a major transcription dysregulation. Importantly, low-dose doxorubicin caused specific changes in the transcriptional profile of several histone deacetylases (HDACs) which are epigenetic regulators of cardiac remodelling. This suggests that cardioprotective therapies, aimed at modulating HDACs during doxorubicin treatment, deserve further exploration.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180571&type=printable |
| spellingShingle | Izabela Piotrowska Mark Isalan Michal Mielcarek Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy. PLoS ONE |
| title | Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy. |
| title_full | Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy. |
| title_fullStr | Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy. |
| title_full_unstemmed | Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy. |
| title_short | Early transcriptional alteration of histone deacetylases in a murine model of doxorubicin-induced cardiomyopathy. |
| title_sort | early transcriptional alteration of histone deacetylases in a murine model of doxorubicin induced cardiomyopathy |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180571&type=printable |
| work_keys_str_mv | AT izabelapiotrowska earlytranscriptionalalterationofhistonedeacetylasesinamurinemodelofdoxorubicininducedcardiomyopathy AT markisalan earlytranscriptionalalterationofhistonedeacetylasesinamurinemodelofdoxorubicininducedcardiomyopathy AT michalmielcarek earlytranscriptionalalterationofhistonedeacetylasesinamurinemodelofdoxorubicininducedcardiomyopathy |