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, Cushman, Sarah, Neufeldt, Dimyana, Rode, Laura, Schmidt, Arne, Juchem, Malte, Leonardy, Julia, Büchler, Gwen, Blume, Jonas, Gern, Olivia Luise, Kalinke, Ulrich, Wen Tan, Wilson Lek, Foo, Roger, Vink, Aryan, van Laake, Linda W., van der Meer, Peter, Bär, Christian, Thum, Thomas |
| المصدر: | Lu , D , Chatterjee , S , Xiao , K , Riedel , I , Huang , C K , Costa , A , Cushman , S , Neufeldt , D , Rode , L , Schmidt , A , Juchem , M , Leonardy , J , Büchler , G , Blume , J , Gern , O L , Kalinke , U , Wen Tan , W L , Foo , R , Vink , A , van Laake , L W , van der Meer , P , Bär , C & Thum , T .... |
| سنة النشر: | 2022 |
| المجموعة: | University of Groningen research database |
| مصطلحات موضوعية: | AAVtherapy, Anti-cancer treatment, Circular RNA, Doxorubicin cardiotoxicity, Heart failure, Mitochondrial metabolism |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://research.rug.nl/en/publications/e61b347c-99bd-45dd-9cdb-80210bdd6280Test |
| DOI: | 10.1093/eurheartj/ehac337 |
| الإتاحة: | https://doi.org/10.1093/eurheartj/ehac337Test https://hdl.handle.net/11370/e61b347c-99bd-45dd-9cdb-80210bdd6280Test https://research.rug.nl/en/publications/e61b347c-99bd-45dd-9cdb-80210bdd6280Test https://pure.rug.nl/ws/files/603591205/ehac337.pdfTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.31198C85 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/eurheartj/ehac337 |
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