Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Circular RNA Circ-INSR - A Novel Target in Doxorubicin-Mediated Cardiotoxicity
D. Lu1, S. Chatterjee1, K. Xiao1, C.-K. Huang1, C. Bär1, T. Thum1, for the study group: IMTTS
1Institut für Molekulare und Translationale Therapiestrategien, OE-8886, Medizinische Hochschule Hannover, Hannover;

Background: Heart failure (HF) is one of the leading causes of death worldwide. A smaller but increasing proportion of HF if caused by anti-cancer treatments. Anti-cancer treatments and subsequently cancer survival significantly improved in the last decades. However, while chemotherapeutic agents such as doxorubicin are very potent cytostatic drugs, they can cause severe acute and chronic cardiotoxicity eventually leading to HF. Circular RNAs (circRNAs) are a novel subclass of non-coding RNA characterized by a covalently closed RNA loop structure. Due to this feature, circRNAs are more stable than linear RNAs suggesting a high value for RNA drug development.

Methods and Results: Using Next Generation Sequencing technology, a highly conserved circular RNA, Circ-INSR, was identified in mouse, rat and human cardiomyocytes. SiRNA mediated circRNA specific knockdown and AAV based circRNA overexpression were applied for loss and gain of function studies. The knock-down of Circ-INSR induced cardiomyocyte metabolic dysfunction and apoptosis. Overexpression of Circ-INSR alleviated doxorubicin-mediated cardiac toxicity both in vitro and in vivo. To investigate the Circ-INSR functional mechanism, RNA-pulldown and mass spectrometry analysis were utilized to further screen for Circ-INSR binding proteins. We observed that Circ-INSR regulates metabolic pathways in cardiomyocytes through a direct interaction with the single-stranded DNA-binding protein (SSBP1). To further improve the value of clinical application, we designed and produced in vitro transcribed human Circ-INSR mimics. Importantly, in vitro transcribed and circularized Circ-INSR mimics but not in vitro transcribed linearized Circ-INSR mimics protected against doxorubicin-induced cardiotoxicity in cardiomyocytes.

Conclusion: Our results highlight Circ-INSR as a promising novel therapeutic or preventive target for anti-cancer drug induced heart failure.


https://dgk.org/kongress_programme/jt2022/aP450.html