دورية أكاديمية
The BET bromodomain inhibitor I-BET-151 induces structural and functional alterations of the heart mitochondria in healthy male mice and rats
| العنوان: | The BET bromodomain inhibitor I-BET-151 induces structural and functional alterations of the heart mitochondria in healthy male mice and rats |
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| المؤلفون: | Piquereau, J, Boet, A, Pechoux, C, Antigny, F, Lambert, M, Gressette, M, Ranchoux, B, Gambaryan, N, Domergue, V, Mumby, S, Montani, D, Adcock, IM, Humbert, M, Garnier, A, Rucker-Martin, C, Perros, F |
| المصدر: | 16 ; 1 |
| بيانات النشر: | MDPI AG |
| سنة النشر: | 2019 |
| المجموعة: | Imperial College London: Spiral |
| مصطلحات موضوعية: | Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemistry & Molecular Biology, Chemistry, Multidisciplinary, bromodomain and extra-terminal domain, bromodomain and extra-terminal domain inhibitor, mitochondria, heart, cardiotoxicity, HDAC INHIBITORS, COMBINING BET, C-MYC, PROTEINS, MELANOMA, STRATEGY, Animals, Electrocardiography, Heterocyclic Compounds, 4 or More Rings, Male, Mice, Inbred C57BL, Organ Specificity, Rats, Wistar |
| الوصف: | The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1422-0067 |
| العلاقة: | International Journal of Molecular Sciences; http://hdl.handle.net/10044/1/77627Test |
| DOI: | 10.3390/ijms20071527 |
| الإتاحة: | https://doi.org/10.3390/ijms20071527Test http://hdl.handle.net/10044/1/77627Test |
| حقوق: | © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0Test/). |
| رقم الانضمام: | edsbas.9EB8294C |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14220067 |
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| DOI: | 10.3390/ijms20071527 |