From the Institute of Molecular and Translational Therapeutic Strategies (S.K.G., A.G., C.B., S.C., A.F., J.F., T.T.) and Excellence Cluster REBIRTH (T.T.), Hannover Medical School, Germany; Herz- und Diabeteszentrum NRW, Universitätsklinikum der Ruhr Universität Bochum, Erich und Hanna Klessmann-Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (H.M.); Clinic for Cardiology and Pneumology, Stem Cell Laboratory, University Medical Center, Gottingen, Germany (K.S.-B.); DZHK (German Center for Cardiovascular Research) Partner site Göttingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.).
Circ Res. 2018 Jan 19;122(2):246-254. doi: 10.1161/CIRCRESAHA.117.311335. Epub 2017 Nov 13.
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.
We aimed to identify key RBPs involved in doxorubicin-mediated heart failure and to elucidate their function.
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 in primary cardiomyocytes increased apoptosis and atrophy after treatment with doxorubicin, whereas lentiviral mediated overexpression of inhibited the doxorubicin-induced apoptosis in cardiomyocytes. In vivo, AAV9 (adeno-associated virus serotype 9)-mediated cardiac overexpression of prevented cardiac apoptosis and cardiac atrophy induced by doxorubicin and improved cardiac function. Mechanistically, by lentiviral-based overexpression and CRISPR/Cas9-mediated silencing of , we identified regulated expression of specific circular RNAs derived from (Titin), (Formin homology 2 domain containing 3), and (Striatin, calmodulin-binding protein 3). Moreover, inhibition of -derived circular RNA increased the susceptibility of cardiomyocytes to doxorubicin.
We here show that overexpression of strongly attenuates the toxic effect of doxorubicin via regulating a set of circular RNAs. is, thus, an interesting target molecule to combat doxorubicin-induced cardiotoxicity.
RNA 结合蛋白（RBPs）已被描述在包括心脏在内的各种器官中表达和调节。然而，关于 RBPs 在阿霉素等化疗药物诱导的心力衰竭中的作用及其与环状 RNA 的相互作用知之甚少。
我们旨在鉴定与阿霉素介导的心力衰竭相关的关键 RBPs，并阐明其功能。
从暴露于阿霉素的鼠心肌中进行的全转录组谱分析鉴定出 5 个差异表达的 RBP。在体外和体内（在小鼠中），阿霉素处理后，RBP QKI（Quaking）在啮齿动物心肌细胞和人诱导多能干细胞衍生的心肌细胞中的表达强烈下调。在原代心肌细胞中敲低 可增加阿霉素处理后的细胞凋亡和萎缩，而慢病毒介导的 过表达则抑制心肌细胞中阿霉素诱导的凋亡。在体内，AAV9（腺相关病毒血清型 9）介导的心脏过表达 可预防阿霉素诱导的心脏凋亡和心脏萎缩，并改善心脏功能。在机制上，通过慢病毒过表达和 CRISPR/Cas9 介导的沉默 ，我们确定了特定环状 RNA 的调节表达，这些环状 RNA 来源于 （肌联蛋白）、 （含formin 同源结构域 2 区的蛋白 3）和 （Striatin，钙调蛋白结合蛋白 3）。此外，抑制 -衍生的环状 RNA 增加了心肌细胞对阿霉素的敏感性。
我们在此表明，过表达 可通过调节一组环状 RNA 强烈减弱阿霉素的毒性作用。因此， 是对抗阿霉素诱导的心脏毒性的一个有趣的靶标分子。
