A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity
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
(2022) European heart journal, volume 43, issue 42, pp. 4496 - 4511
(Article)
Abstract
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
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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.
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Keywords: AAVtherapy, Animals, Anti-cancer treatment, Apoptosis, Cardiotoxicity/etiology, Circular RNA, DNA-Binding Proteins/metabolism, Doxorubicin cardiotoxicity, Doxorubicin/toxicity, Heart Diseases/chemically induced, Heart failure, Humans, Mice, Mitochondrial Proteins, Mitochondrial metabolism, Myocytes, Cardiac/metabolism, Proteomics, RNA, Circular/genetics, Receptor, Insulin/genetics, Journal Article
ISSN: 0195-668X
Publisher: Oxford University Press
Note: Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press on behalf of European Society of Cardiology.
(Peer reviewed)