PMID- 29133306 OWN - NLM STAT- MEDLINE DCOM- 20190619 LR - 20221109 IS - 1524-4571 (Electronic) IS - 0009-7330 (Print) IS - 0009-7330 (Linking) VI - 122 IP - 2 DP - 2018 Jan 19 TI - Quaking Inhibits Doxorubicin-Mediated Cardiotoxicity Through Regulation of Cardiac Circular RNA Expression. PG - 246-254 LID - 10.1161/CIRCRESAHA.117.311335 [doi] AB - 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. CI - (c) 2017 The Authors. FAU - Gupta, Shashi Kumar AU - Gupta SK AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). gupta.shashi@mh-hannover.de thum.thomas@mh-hannover.de. FAU - Garg, Ankita AU - Garg A AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). FAU - Bar, Christian AU - Bar C AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). FAU - Chatterjee, Shambhabi AU - Chatterjee S AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). FAU - Foinquinos, Ariana AU - Foinquinos A AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). FAU - Milting, Hendrik AU - Milting H AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). FAU - Streckfuss-Bomeke, Katrin AU - Streckfuss-Bomeke K AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). FAU - Fiedler, Jan AU - Fiedler J AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). FAU - Thum, Thomas AU - Thum T AD - 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, Universitatsklinikum der Ruhr Universitat 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 Gottingen, Germany (K.S.-B.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.). gupta.shashi@mh-hannover.de thum.thomas@mh-hannover.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171113 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Qk protein, mouse) RN - 0 (RNA, Circular) RN - 0 (RNA-Binding Proteins) RN - 63231-63-0 (RNA) RN - 80168379AG (Doxorubicin) SB - IM CIN - Circ Res. 2018 Jan 19;122(2):188-190. PMID: 29348242 MH - Animals MH - Antibiotics, Antineoplastic/*toxicity MH - Cardiotoxicity/genetics/*metabolism MH - Doxorubicin/*toxicity MH - Gene Expression MH - Mice MH - Mice, Inbred C57BL MH - Myocytes, Cardiac/drug effects/metabolism MH - RNA/*biosynthesis/genetics MH - RNA, Circular MH - RNA-Binding Proteins/*biosynthesis/genetics MH - Random Allocation PMC - PMC5771684 OTO - NOTNLM OT - RNA-binding protein OT - cardiotoxicity OT - doxorubicin OT - heart failure OT - noncoding RNA EDAT- 2017/11/15 06:00 MHDA- 2019/06/20 06:00 PMCR- 2018/01/17 CRDT- 2017/11/15 06:00 PHST- 2017/05/13 00:00 [received] PHST- 2017/11/09 00:00 [revised] PHST- 2017/11/10 00:00 [accepted] PHST- 2017/11/15 06:00 [pubmed] PHST- 2019/06/20 06:00 [medline] PHST- 2017/11/15 06:00 [entrez] PHST- 2018/01/17 00:00 [pmc-release] AID - CIRCRESAHA.117.311335 [pii] AID - 10.1161/CIRCRESAHA.117.311335 [doi] PST - ppublish SO - Circ Res. 2018 Jan 19;122(2):246-254. doi: 10.1161/CIRCRESAHA.117.311335. Epub 2017 Nov 13.