Rationale: RBPs (RNA-binding proteins) have been described to be expressed and regulated in various organs including the heart. Little is known about the role of RBPs in heart failure induced by the chemotherapy drug doxorubicin and their interaction with circular RNAs.

Objective: We aimed to identify key RBPs involved in doxorubicin-mediated heart failure and to elucidate their function.

Methods and Results: Global transcriptome profiling from murine myocardium exposed to doxorubicin identified 5 differentially expressed RBPs. Expression of the RBP QKI (Quaking) in response to doxorubicin was strongly downregulated in rodent cardiomyocytes and human induced pluripotent stem cell–derived cardiomyocytes in vitro and in vivo in mice. Knockdown of Qki in primary cardiomyocytes increased apoptosis and atrophy after treatment with doxorubicin, whereas lentiviral mediated overexpression of Qki5 inhibited the doxorubicin-induced apoptosis in cardiomyocytes. In vivo, AAV9 (adeno-associated virus serotype 9)–mediated cardiac overexpression of Qki5 prevented cardiac apoptosis and cardiac atrophy induced by doxorubicin and improved cardiac function. Mechanistically, by lentiviral-based overexpression and CRISPR/Cas9-mediated silencing of Qki5, we identified regulated expression of specific circular RNAs derived from Ttn (Titin), Fhod3 (Formin homology 2 domain containing 3), and Strn3 (Striatin, calmodulin-binding protein 3). Moreover, inhibition of Ttn-derived circular RNA increased the susceptibility of cardiomyocytes to doxorubicin.

Conclusions: We here show that overexpression of Qki5 strongly attenuates the toxic effect of doxorubicin via regulating a set of circular RNAs. Qki5 is, thus, an interesting target molecule to combat doxorubicin-induced cardiotoxicity.

原理：已经描述了RBP（RNA结合蛋白）在包括心脏在内的各种器官中表达和调节。关于RBP在由化疗药物阿霉素引起的心力衰竭中的作用及其与环状RNA的相互作用了解甚少。

Objective: We aimed to identify key RBPs involved in doxorubicin-mediated heart failure and to elucidate their function.

方法和结果：暴露于阿霉素的鼠心肌整体转录组谱分析确定了5个差异表达的RBP。在小鼠体内和体外，在啮齿动物的心肌细胞和人诱导的多能干细胞衍生的心肌细胞中，RBP QKI（Quaking）的表达均强烈下调了对阿霉素的反应。在用阿霉素治疗后，在原代心肌细胞中敲除Qki会增加细胞凋亡和萎缩，而慢病毒介导的Qki5的过表达抑制阿霉素诱导的心肌细胞凋亡。在体内，AAV9（腺相关病毒血清型9）介导的Qki5心脏过度表达预防了由阿霉素引起的心脏细胞凋亡和心脏萎缩，并改善了心脏功能。从机制上讲，通过基于慢病毒的过表达和CRISPR / Cas9介导的Qki5沉默，我们鉴定了源自Ttn（Titin），Fhod3（含2的Formin同源2域）和Strn3（Striatin，钙调蛋白结合）的特定环状RNA的调控表达蛋白质3）。此外，抑制Ttn衍生的环状RNA增加了心肌细胞对阿霉素的敏感性。

结论：我们在这里表明Qki5的过表达通过调节一组环状RNA强烈减弱了阿霉素的毒性作用。因此， Qki5是对抗阿霉素诱导的心脏毒性的有趣靶分子。