title: MicroRNA-377 Mediates Cardiomyocyte Apoptosis Induced by Cyclosporin A.
abstract: Cyclosporin A (CsA) is a potent immunosuppressant that has wide clinical applications for autoimmune disorders and prevention of rejection in organ transplantation. However, its liver, kidney, and heart toxicity has limited its use. In this study, we investigated the mechanism by which CsA induced cardiomyocyte apoptosis. Through microarray analysis, we found that the expression of microRNA (miR)-377 was regulated by CsA. Ectopic overexpression of miR-377 led to increased apoptosis in cardiomyocytes, as evidenced by an increased number of apoptotic cells, increased levels of proapoptotic proteins, decreased levels of antiapoptotic proteins, and elevated caspase pathway activity. We also found that miR-377 was required for CsA-induced apoptosis, because inhibition of miR-377 expression markedly reduced the ability of CsA to induce cardiomyocyte apoptosis. In addition, we identified XIAP and NRP2 as direct targets for miR-377. The expression levels of these 2 antiapoptotic proteins were negatively regulated by miR-377, as well as by CsA both in vitro and in vivo. Our data suggested that CsA induced cardiomyocyte apoptosis through the miR-377-XIAP/NRP2 axis.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xiao-Duo
authors.initials: XD
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jin-Yu
authors.initials: JY
authors.lastname: Chi
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, China.
authors.forename: Hai-Hai
authors.initials: HH
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, China.
authors.forename: Long-Tao
authors.initials: LT
authors.lastname: Huangfu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Zi-Dan
authors.initials: ZD
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Heilongjiang Provincial Hospital, Harbin, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: xinhua_yin@163.com.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Yin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D035683:MicroRNAs / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D039943:Neuropilin-2 / Q000378:metabolism; D017208:Rats, Wistar; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; C534063:MIRN377 microRNA, human; D035683:MicroRNAs; D039943:Neuropilin-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C581308:neuropilin-2, human; D016572:Cyclosporine