Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Eur Heart J. 2022 Nov 7;43(42):4496-4511. doi: 10.1093/eurheartj/ehac337.
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.
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.
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.
导致心力衰竭（HF）的心脏毒性是许多癌症幸存者日益严重的问题。由于没有特定的治疗策略，因此采用了 RNA 发现途径，并开发了一种新的、强大的基于环状 RNA（circRNA）的疗法来治疗多柔比星诱导的 HF。
应用 circRNA 测序，鉴定出高度种属保守的胰岛素受体环状 RNA（Circ-INSR），它参与 HF 过程，包括由心脏毒性抗癌治疗引起的过程。化疗引起的心脏毒性导致啮齿动物和患者的 Circ-INSR 下调，这在机制上导致心肌细胞死亡、心脏功能障碍和线粒体损伤。相比之下，Circ-INSR 过表达可防止多柔比星在体外和慢性多柔比星心脏毒性的小鼠模型中诱导的啮齿动物和人类心肌细胞的心脏毒性。乳腺癌 1 型易感性蛋白（Brca1）被鉴定为 Circ-INSR 表达的调节因子。详细的转录组和蛋白质组分析表明，Circ-INSR 调节心肌细胞中的凋亡和代谢途径。Circ-INSR 与单链 DNA 结合蛋白（SSBP1）相互作用，介导其在多柔比星应激下的心脏保护作用。重要的是，体外转录和环化的 Circ-INSR 模拟物也能防止多柔比星引起的心脏毒性。
Circ-INSR 是一种高度保守的非编码 RNA，在心脏毒性和心脏重塑过程中下调。腺相关病毒和基于 circRNA 模拟物的 Circ-INSR 过表达可预防和逆转多柔比星诱导的心肌细胞死亡，改善心脏功能。这项研究的结果突出了一种新的、具有转化意义的基于 Circ-INSR 的治疗多柔比星诱导心脏功能障碍的方法。
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