Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes
BackgroundChronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2016-01-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.115.002383 |
| _version_ | 1818328035187752960 |
|---|---|
| author | Paola Altieri Chiara Barisione Edoardo Lazzarini Anna Garuti Gian Paolo Bezante Marco Canepa Paolo Spallarossa Carlo Gabriele Tocchetti Sveva Bollini Claudio Brunelli Pietro Ameri |
| author_facet | Paola Altieri Chiara Barisione Edoardo Lazzarini Anna Garuti Gian Paolo Bezante Marco Canepa Paolo Spallarossa Carlo Gabriele Tocchetti Sveva Bollini Claudio Brunelli Pietro Ameri |
| author_sort | Paola Altieri |
| collection | DOAJ |
| description | BackgroundChronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long‐term anthracycline cardiomyopathy. Methods and ResultsH9c2 cells and neonatal mouse cardiomyocytes were exposed to doxorubicin with or without prior incubation with testosterone or 17β‐estradiol, the main androgen and estrogen, respectively. Testosterone, but not 17β‐estradiol, counteracted doxorubicin‐elicited senescence. Downregulation of telomere binding factor 2, which has been pinpointed previously as being pivotal to doxorubicin‐induced senescence, was also prevented by testosterone, as were p53 phosphorylation and accumulation. Pretreatment with the androgen receptor antagonist flutamide, the phosphatidylinositol 3 kinase inhibitor LY294002, and the nitric oxide synthase inhibitor L‐NG‐nitroarginine methyl ester abrogated the reduction in senescence and the normalization of telomere binding factor 2 levels attained by testosterone. Consistently, testosterone enhanced the phosphorylation of AKT and nitric oxide synthase 3. In H9c2 cells, doxorubicin‐stimulated senescence was still observed up to 21 days after treatment and increased further when cells were rechallenged with doxorubicin 14 days after the first exposure to mimic the schedule of anthracycline‐containing chemotherapy. Remarkably, these effects were also inhibited by testosterone. ConclusionsTestosterone protects cardiomyocytes against senescence caused by doxorubicin at least in part by modulating telomere binding factor 2 via a pathway involving the androgen receptor, phosphatidylinositol 3 kinase, AKT, and nitric oxide synthase 3. This is a potential mechanism by which pubescent and adolescent boys are less prone to chronic anthracycline cardiotoxicity than girls. |
| first_indexed | 2024-12-13T12:25:45Z |
| format | Article |
| id | doaj.art-67d0fb22b0b8492b8204b08f6a22c4bb |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-13T12:25:45Z |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-67d0fb22b0b8492b8204b08f6a22c4bb2022-12-21T23:46:19ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802016-01-015110.1161/JAHA.115.002383Testosterone Antagonizes Doxorubicin‐Induced Senescence of CardiomyocytesPaola Altieri0Chiara Barisione1Edoardo Lazzarini2Anna Garuti3Gian Paolo Bezante4Marco Canepa5Paolo Spallarossa6Carlo Gabriele Tocchetti7Sveva Bollini8Claudio Brunelli9Pietro Ameri10Laboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyLaboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyLaboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyLaboratory of Cellular Therapies, Department of Internal Medicine, University of Genova, ItalyLaboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyLaboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyLaboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyDivision of Internal Medicine, Department of Translational Medical Sciences, Federico II University, Napoli, ItalyRegenerative Medicine Laboratory, Department of Experimental Medicine, University of Genova, ItalyLaboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyLaboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, ItalyBackgroundChronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long‐term anthracycline cardiomyopathy. Methods and ResultsH9c2 cells and neonatal mouse cardiomyocytes were exposed to doxorubicin with or without prior incubation with testosterone or 17β‐estradiol, the main androgen and estrogen, respectively. Testosterone, but not 17β‐estradiol, counteracted doxorubicin‐elicited senescence. Downregulation of telomere binding factor 2, which has been pinpointed previously as being pivotal to doxorubicin‐induced senescence, was also prevented by testosterone, as were p53 phosphorylation and accumulation. Pretreatment with the androgen receptor antagonist flutamide, the phosphatidylinositol 3 kinase inhibitor LY294002, and the nitric oxide synthase inhibitor L‐NG‐nitroarginine methyl ester abrogated the reduction in senescence and the normalization of telomere binding factor 2 levels attained by testosterone. Consistently, testosterone enhanced the phosphorylation of AKT and nitric oxide synthase 3. In H9c2 cells, doxorubicin‐stimulated senescence was still observed up to 21 days after treatment and increased further when cells were rechallenged with doxorubicin 14 days after the first exposure to mimic the schedule of anthracycline‐containing chemotherapy. Remarkably, these effects were also inhibited by testosterone. ConclusionsTestosterone protects cardiomyocytes against senescence caused by doxorubicin at least in part by modulating telomere binding factor 2 via a pathway involving the androgen receptor, phosphatidylinositol 3 kinase, AKT, and nitric oxide synthase 3. This is a potential mechanism by which pubescent and adolescent boys are less prone to chronic anthracycline cardiotoxicity than girls.https://www.ahajournals.org/doi/10.1161/JAHA.115.002383cardiotoxicitydoxorubicinsenescencesextestosterone |
| spellingShingle | Paola Altieri Chiara Barisione Edoardo Lazzarini Anna Garuti Gian Paolo Bezante Marco Canepa Paolo Spallarossa Carlo Gabriele Tocchetti Sveva Bollini Claudio Brunelli Pietro Ameri Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cardiotoxicity doxorubicin senescence sex testosterone |
| title | Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes |
| title_full | Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes |
| title_fullStr | Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes |
| title_full_unstemmed | Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes |
| title_short | Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes |
| title_sort | testosterone antagonizes doxorubicin induced senescence of cardiomyocytes |
| topic | cardiotoxicity doxorubicin senescence sex testosterone |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.115.002383 |
| work_keys_str_mv | AT paolaaltieri testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT chiarabarisione testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT edoardolazzarini testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT annagaruti testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT gianpaolobezante testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT marcocanepa testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT paolospallarossa testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT carlogabrieletocchetti testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT svevabollini testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT claudiobrunelli testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes AT pietroameri testosteroneantagonizesdoxorubicininducedsenescenceofcardiomyocytes |