Abstract
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.
Highlights
Rationale: RBPs (RNA-binding proteins) have been described to be expressed and regulated in various organs including the heart
AAV9–mediated cardiac overexpression of Qki[5] prevented cardiac apoptosis and cardiac atrophy induced by doxorubicin and improved cardiac function
Inhibition of Ttn-derived circular RNA increased the susceptibility of cardiomyocytes to doxorubicin
Summary
The authors declare that all supporting data are available within the article (and its Online Data Supplement). C57BL/6 N mice of 10 to 12 weeks of age were injected (intraperitoneally) with doxorubicin at a dose of 5 mg/kg once a week for consecutive 5 weeks. One week later after the last doxorubicin treatment, echocardiography data were recorded by an independent blinded researcher using the Vevo 2100 system (Fujifilm Visulasonics, Inc). Hearts were harvested and processed for further molecular and cellular assays. Echocardiography data were analyzed using standard imaging protocols (M-mode and B-mode) for global cardiac volumes and functioning using the Vevostrain software (Fujifilm Visulasonics, Inc). Animal experiments were approved by the local authorities at Hannover Medical School and Niedersachsen Landesamt für Verbraucherschutz. AAV9 (adeno-associated virus serotype 9) was injected (intravenously) 1 week before first doxorubicin injection. Animal experiments were randomized and blinded with an internal number
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