title: MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD.
abstract: BACKGROUND
  Necrosis is one of the main forms of cardiomyocyte death in heart disease. Recent studies have demonstrated that certain types of necrosis are regulated and programmed dependent on the activation of receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3 which may be negatively regulated by Fas-associated protein with death domain (FADD). In addition, microRNAs and long noncoding RNAs have been shown to play important roles in various biological processes recently.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that microRNA-103/107 and H19 can participate in the regulation of RIPK1- and RIPK3-dependent necrosis in fetal cardiomyocyte-derived H9c2 cells and myocardial infarction through targeting FADD.
  
  
  RESULTS
  Our results show that FADD participates in H2O2-induced necrosis by influencing the formation of RIPK1 and RIPK3 complexes in H9c2 cells. We further demonstrate that miR-103/107 target FADD directly. Knockdown of miR-103/107 antagonizes necrosis in the cellular model and also myocardial infarction in a mouse ischemia/reperfusion model. The miR-103/107-FADD pathway does not participate in tumor necrosis factor-α-induced necrosis. In exploring the molecular mechanism by which miR-103/107 are regulated, we show that long noncoding RNA H19 directly binds to miR-103/107 and regulates FADD expression and necrosis.
  
  
  CONCLUSIONS
  Our results reveal a novel myocardial necrosis regulation model, which is composed of H19, miR-103/107, and FADD. Modulation of their levels may provide a new approach for preventing myocardial necrosis.
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Jian-Xun
authors.initials: JX
authors.lastname: Wang
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Jian-Qin
authors.initials: JQ
authors.lastname: Jiao
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Chang
authors.initials: C
authors.lastname: Feng
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Sun
authors.initials: S
authors.lastname: Teng
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Lu-Yu
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Gong
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Zhi-Xia
authors.initials: ZX
authors.lastname: Zhou
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.).
authors.forename: Jian-Ling
authors.initials: JL
authors.lastname: Wang
authors.affiliation: From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.). peifli@qdu.edu.cn.
authors.forename: Pei-feng
authors.initials: PF
authors.lastname: Li
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D009841:Oligonucleotides / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D051381:Rats; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; C094335:H19 long non-coding RNA; C000602463:MIRN103 microRNA, rat; C579315:MIRN107 microRNA, rat; D035683:MicroRNAs; D009841:Oligonucleotides; D062085:RNA, Long Noncoding; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C582791:Ripk3 protein, rat
keywords: Fas-associated death domain protein; H19 long noncoding RNA; ischemia/reperfusion injury; miRNA; myocardial infarction; necrosis; oxidative stress