Circular RNAs at the intersection of cancer and heart disease: potential therapeutic targets in cardio-oncology.

Considerable progress has been made in managing cancer; however, with these advancements comes the discovery of previously unknown adverse events. In particular, the prolonged lifespan of patients has uncovered severe cardiotoxic side effects of widely used anti-cancer therapies, which restrict their administration and thus compromise the success of the seemingly most suitable treatments in large cancer patient cohorts. Vice versa, cardiovascular diseases can also promote both the onset and progression of different cancers, highlighting that both conditions are deeply interlinked. Recognizing these close interactions, the novel interdisciplinary field of cardio-oncology has emerged to closely study these uniquely correlating diseases. In this regard, non-coding RNAs (ncRNAs) are gaining increasing attention since they constitute crucial regulators in many physiological but also pathological signalling pathways, including those of cancer and cardiac dysfunction. In this review, we focus on the new subtype of ncRNA, circular RNAs, in their distinct exchange within cardio-oncology and discuss their suitability as potent targets for the simultaneous treatment of cardiac dysfunction and cancer.

A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity.

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.