title: MicroRNA-146a Induces Lineage-Negative Bone Marrow Cell Apoptosis and Senescence by Targeting Polo-Like Kinase 2 Expression.
abstract: OBJECTIVE
  Lineage-negative bone marrow cells (lin- BMCs) are enriched in endothelial progenitor cells and mediate vascular repair. Aging-associated senescence and apoptosis result in reduced number and functionality of lin- BMCs, impairing their prorepair capacity. The molecular mechanisms underlying lin- BMC senescence and apoptosis are poorly understood. MicroRNAs (miRNAs) regulate many important biological processes. The identification of miRNA-mRNA networks that modulate the health and functionality of lin- BMCs is a critical step in understanding the process of vascular repair. The aim of this study was to characterize the role of the miR-146a-Polo-like kinase 2 (Plk2) network in regulating lin- BMC senescence, apoptosis, and their angiogenic capability.
  
  
  RESULTS
  Transcriptome analysis in lin- BMCs isolated from young and aged wild-type and ApoE-/-(apolipoprotein E) mice showed a significant age-associated increase in miR-146a expression. In silico analysis, expression study and Luciferase reporter assay established Plk2 as a direct target of miR-146a. miR-146a overexpression in young lin- BMCs inhibited Plk2 expression, resulting in increased senescence and apoptosis, via p16Ink4a/p19Arf and p53, respectively, as well as impaired angiogenic capacity in vitro and in vivo. Conversely, suppression of miR-146a in aged lin- BMCs increased Plk2 expression and rejuvenated lin- BMCs, resulting in decreased senescence and apoptosis, leading to improved angiogenesis.
  
  
  CONCLUSIONS
  (1) miR-146a regulates lin- BMC senescence and apoptosis by suppressing Plk2 expression that, in turn, activates p16Ink4a/p19Arf and p53 and (2) modulation of miR-146a or its target Plk2 may represent a potential therapeutic intervention to improve lin- BMC-mediated angiogenesis and vascular repair.
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Shanming
authors.initials: S
authors.lastname: Deng
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Huilan
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Chunling
authors.initials: C
authors.lastname: Jia
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Shoukang
authors.initials: S
authors.lastname: Zhu
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Xianming
authors.initials: X
authors.lastname: Chu
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Jianqin
authors.initials: J
authors.lastname: Wei
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Emily
authors.initials: E
authors.lastname: Chen
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Conrad J
authors.initials: CJ
authors.lastname: Macon
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Dushyantha T
authors.initials: DT
authors.lastname: Jayaweera
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.).
authors.forename: Derek M
authors.initials: DM
authors.lastname: Dykxhoorn
authors.affiliation: From the Department of Medicine (S.D., H.W., C.J., S.Z., X.C., Q.M., J.W., E.C., W.Z., C.J.M., D.T.J, C.D.) and John T. Macdonald Foundation Department of Human Genetics (D.M.D.), Miller School of Medicine, University of Miami, FL; and Department of Cardiology, The Affiliated Hospital of Qingdao University, China (X.C.). cdong3@med.miami.edu.
authors.forename: Chunming
authors.initials: C
authors.lastname: Dong
mesh_terms: D020413:3' Untranslated Regions; D000367:Age Factors; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000201:enzymology* / Q000473:pathology; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015536:Down-Regulation; D066026:Endothelial Progenitor Cells / Q000201:enzymology* / Q000473:pathology; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D059467:Transcriptome; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D001057:Apolipoproteins E; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C444640:serum-inducible kinase
keywords: apoptosis; cardiovascular diseases; mice; microRNAs; progenitor cells