title: MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.
abstract: Doxorubicin (DOX) is a wide-spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. However, the mechanisms underlying DOX-induced cardiomyopathy remain mostly unclear. Here we observed that apoptosis repressor with caspase recruitment domain (ARC) was downregulated in mouse heart and cardiomyocytes upon DOX treatment. Furthermore, enforced expression of ARC attenuated DOX-induced cardiomyocyte mitochondrial fission and apoptosis. ARC transgenic mice demonstrated reduced cardiotoxicity upon DOX administration. DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1). In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis. MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells. Taken together, these findings provide novel evidence that miR-532-3p and ARC constitute an antiapoptotic pathway that regulates DOX cardiotoxicity. Therefore, the development of new therapeutic strategies based on ARC and miR-532-3p is promising for overcoming the cardiotoxicity of chemotherapy for cancer therapy.
authors.affiliation: 1] National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [2] Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
authors.forename: J-X
authors.initials: JX
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Feng
authors.affiliation: National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Sun
authors.affiliation: Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.affiliation: Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: 1] National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [2] Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China [3] College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: P-F
authors.initials: PF
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004317:Doxorubicin / Q000633:toxicity*; D034281:Dynamins; D020558:GTP Phosphohydrolases; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000502:physiology; D024101:Mitochondrial Proteins; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*
chemical_list: C585583:MIRN532 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D004317:Doxorubicin; D020169:Caspases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins