Quaking Inhibits Doxorubicin-Mediated Cardiotoxicity Through Regulation of Cardiac Circular RNA Expression.
Quaking Inhibits Doxorubicin-Mediated Cardiotoxicity Through Regulation of Cardiac Circular RNA Expression.
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Quaking 通过调节心脏循环 RNA 表达来抑制多柔比星介导的心脏毒性。
DOI：
10.1161/circresaha.117.311335
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发表时间：
2018-01-19
影响因子：
20.1
通讯作者：
Thum T
中科院分区：
文献类型：
--
作者：
Gupta SK;Garg A;Bär C;Chatterjee S;Foinquinos A;Milting H;Streckfuß-Bömeke K;Fiedler J;Thum T
补充数字内容可在文本中找到。RBP（RNA结合蛋白）已被描述为在包括心脏在内的各种器官中表达和调节。RBP在化疗药物阿霉素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。我们的目的是确定参与阿霉素介导的心力衰竭的关键RBP，并阐明其功能。从暴露于阿霉素的小鼠心肌的全局转录组分析鉴定了5种差异表达的RBP。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，RBP QKI（Quaking）在小鼠体内和体外对阿霉素的反应表达强烈下调。在原代心肌细胞中敲除Qki增加了阿霉素治疗后的凋亡和萎缩，而慢病毒介导的Qki 5过表达抑制了阿霉素诱导的心肌细胞凋亡。在体内，AAV 9（腺相关病毒血清型9）介导的Qki 5的心脏过表达防止了阿霉素诱导的心脏凋亡和心脏萎缩，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Qki 5沉默，我们鉴定了来自Ttn（Titin）、Fhod 3（包含3的形成蛋白同源性2结构域）和Strn 3（Striatin，钙调蛋白结合蛋白3）的特异性环状RNA的调节表达。此外，Ttn衍生的环状RNA的抑制增加了心肌细胞对阿霉素的敏感性。我们在这里表明，过表达Qki 5强烈减弱阿霉素的毒性作用，通过调节一组环状RNA。因此，Qki 5是对抗阿霉素诱导的心脏毒性的有趣的靶分子。
Supplemental Digital Content is available in the text. 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 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. 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.