title: miR-874 regulates myocardial necrosis by targeting caspase-8.
abstract: Cardiomyocyte death is an important reason for the cardiac syndromes, such as heart failure (HF) and myocardial infarction (MI). In the heart diseases, necrosis is one of the main forms of cell death. MicroRNAs (miRNAs) are a class of small non-coding RNAs that mediate post-transcriptional gene silencing. Hitherto, it is not yet clear whether miRNA can regulate necrosis in cardiomyocyte. In this work, we performed a microarray to detect miRNAs in response to H2O2 treatment, and the results showed that miR-874 was substantially increased. We further studied the function of miR-874, and observed that knockdown of miR-874 attenuated necrosis in the cellular model and also MI in the animal model. We searched for the downstream mediator of miR-874 and identified that caspase-8 was a target of miR-874. Caspase-8 was able to antagonize necrosis. When suppressed by miR-874, caspase-8 lost the ability to repress necrotic program. In exploring the molecular mechanism by which miR-874 expression is regulated, we identified that Foxo3a could transcriptionally repress miR-874 expression. Foxo3a transgenic or knockout mice exhibited a low or high expression level of miR-874, and a reduced or enhanced necrosis and MI. Our present study reveals a novel myocardial necrotic regulating model, which is composed of Foxo3a, miR-874 and caspase-8. Modulation of their levels may provide a new approach for tackling myocardial necrosis.
authors.affiliation: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.forename: L-Y
authors.initials: LY
authors.lastname: Zhou
authors.forename: S-L
authors.initials: SL
authors.lastname: Ding
authors.forename: B
authors.initials: B
authors.lastname: Long
authors.forename: C-Y
authors.initials: CY
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Sun
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Fan
authors.forename: L
authors.initials: L
authors.lastname: Sun
authors.forename: P-F
authors.initials: PF
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004794:Enzyme Repression; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D009336:Necrosis; D016877:Oxidants / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034622:RNA Interference
chemical_list: D020413:3' Untranslated Regions; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C586538:MIRN874 microRNA, mouse; D035683:MicroRNAs; D016877:Oxidants; D006861:Hydrogen Peroxide; C505526:Casp8 protein, mouse; D053181:Caspase 8