Telomerase therapy attenuates cardiotoxic effects of doxorubicin
| Autor: | Shashi Kumar Gupta, Emiliano Bolesani, Thomas Thum, Shambhabi Chatterjee, Katrin Streckfuss-Bömeke, Alessia Costa, Christian Bär, Diego Megias, Dongchao Lu, Sandor Batkai, Christina Brandenberger, Teresa Hofer, Robert Zweigerdt |
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| Přispěvatelé: | Publica |
| Rok vydání: | 2021 |
| Předmět: |
Telomerase
Cell division Genetic enhancement Genetic Vectors Induced Pluripotent Stem Cells Apoptosis Mitochondrion Gene Expression Regulation Enzymologic Mice 03 medical and health sciences 0302 clinical medicine Neoplasms Drug Discovery Genetics Animals Humans Medicine Myocytes Cardiac Doxorubicin Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences Cardiotoxicity business.industry Dependovirus Mitochondria 3. Good health Telomere 030220 oncology & carcinogenesis Commentary Cancer research Molecular Medicine Reactive Oxygen Species business Signal Transduction medicine.drug |
| Zdroj: | Molecular Therapy Mol Ther |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2020.12.035 |
| Popis: | Doxorubicin is one of the most potent chemotherapeutic agents. However, its clinical use is restricted due to the severe risk of cardiotoxicity, partially attributed to elevated production of reactive oxygen species (ROS). Telomerase canonically maintains telomeres during cell division but is silenced in adult hearts. In non-dividing cells such as cardiomyocytes, telomerase confers pro-survival traits, likely owing to the detoxification of ROS. Therefore, we hypothesized that pharmacological overexpression of telomerase may be used as a therapeutic strategy for the prevention of doxorubicin-induced cardiotoxicity. We used adeno-associated virus (AAV)-mediated gene therapy for long-term expression of telomerase in in vitro and in vivo models of doxorubicin-induced cardiotoxicity. Overexpression of telomerase protected the heart from doxorubicin-mediated apoptosis and rescued cardiac function, which was accompanied by preserved cardiomyocyte size. At the mechanistic level, we observed altered mitochondrial morphology and dynamics in response to telomerase expression. Complementary in vitro experiments confirmed the anti-apoptotic effects of telomerase overexpression in human induced pluripotent stem cell-derived cardiomyocytes after doxorubicin treatment. Strikingly, elevated levels of telomerase translocated to the mitochondria upon doxorubicin treatment, which helped to maintain mitochondrial function. Thus, telomerase gene therapy could be a novel preventive strategy for cardiotoxicity by chemotherapy agents such as the anthracyclines. |
| Databáze: | OpenAIRE |
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