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

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.

Circular RNAs in diabetes and its complications: Current knowledge and future prospects

“…The PAE-siRNA complex could downregulate circMDK and inhibit hepatocellular carcinoma without obvious side effects in tumor models. Additionally, in vitro transcribed circ-INSR mimics effectively prevented doxorubicin-induced cardiotoxicity, which provides an exciting complementary option for adeno-associated virus-based therapies ( Lu et al, 2022 ).…”

The year in cardiovascular medicine 2022: the top 10 papers in cardio-oncology

“…Innovative cardioprotective strategies beyond standard CV medications are also being investigated. In an elegant set of studies, Lu et al 4 found that doxorubicin leads to the down-regulation of circular RNA derived from the insulin receptor (Circ-INSR) locus in the heart. Circ-INSR binds to the mitochondrial single-stranded DNA-binding protein, preserving mitochondrial DNA stability and replication and ultimately mitochondrial function and structure.…”

CircSMARCA5: A key circular RNA in various human diseases

“…With more research to carry out on circSMARCA5 in other diseases, our understanding of the pathogenic mechanism of circSMARCA5 will become more complete. Furthermore, with the advent of technology of synthetic circRNAs in vitro ( Lu et al, 2022 ; Qu et al, 2022 ), synthetic drugs targeted circSMARCA5 may become a therapeutic option for some cancers in the future.…”