دورية أكاديمية
A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity
| العنوان: | A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity |
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| المؤلفون: | Lu, Dongchao, Chatterjee, Shambhabi, Xiao, Ke, Riedel, Isabelle, Huang, Cheng-Kai, Costa, Alessia, Neufeldt, Dimyana, Cushman, Sarah, Rode, Laura, Schmidt, Arne, Juchem, Malte, Leonardy, Julia, Büchler, Gwen, Blume, Jonas, Gern, Olivia-Luise, Kalinke, Ulrich, Tan, Wilson Lek Wen, Foo, Roger, Vink, Aryan, Laake, Linda W. van, Meer, Peter van der, Bär, Christian, Thum, Thomas |
| سنة النشر: | 2022 |
| المجموعة: | Publikationsdatenbank der Fraunhofer-Gesellschaft |
| الوصف: | 4496 ; 4511 ; Aims: Cardiotoxicity leading to heart failure (HF) is a growing problem in many cancer survivors. As specific treatment strategies are not available, RNA discovery pipelines were employed and a new and powerful circular RNA (circRNA)-based therapy was developed for the treatment of doxorubicin-induced HF. Methods and results: The circRNA sequencing was applied and the highly species-conserved circRNA insulin receptor (Circ-INSR) was identified, which participates in HF processes, including those provoked by cardiotoxic anti-cancer treatments. Chemotherapy-provoked cardiotoxicity leads to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributes to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity. Conclusion: Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction. ; 43 ; 42 |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0195-668X |
| العلاقة: | European Heart Journal; https://publica.fraunhofer.de/handle/publica/440358Test |
| DOI: | 10.1093/eurheartj/ehac337 |
| الإتاحة: | https://doi.org/10.1093/eurheartj/ehac337Test https://publica.fraunhofer.de/handle/publica/440358Test |
| رقم الانضمام: | edsbas.7947768C |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 0195668X |
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| DOI: | 10.1093/eurheartj/ehac337 |