A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity . (27th June 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: European heart journal. Volume 43:Number 42(2022)
• Page Start: 4496
• Page End: 4511
• Publication Date: 2022-06-27
• Subjects: Heart failure Circular RNA Doxorubicin cardiotoxicity AAVtherapy Mitochondrial metabolism Anti-cancer treatment; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac337
• Languages: English
• ISSNs: 0195-668X

Abstract

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 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. Structured Graphical Abstract: Structured Graphical Abstract Circular RNA therapy for cardioprotection. AAV, adeno-associated virus; INSR, insulin receptor; SSBP1, single-stranded DNA-binding protein.