Shanming Deng1, Huilan Wang1, Chunling Jia1, Shoukang Zhu1, Xianming Chu1, Qi Ma1, Jianqin Wei1, Emily Chen1, Wei Zhu1, Conrad J Macon1, Dushyantha T Jayaweera1, Derek M Dykxhoorn1, Chunming Dong2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Reinier A Boon; Kazuma Iekushi; Stefanie Lechner; Timon Seeger; Ariane Fischer; Susanne Heydt; David Kaluza; Karine Tréguer; Guillaume Carmona; Angelika Bonauer; Anton J G Horrevoets; Nathalie Didier; Zenawit Girmatsion; Peter Biliczki; Joachim R Ehrlich; Hugo A Katus; Oliver J Müller; Michael Potente; Andreas M Zeiher; Heiko Hermeking; Stefanie Dimmeler Journal: Nature Date: 2013-02-20 Impact factor: 49.962
Authors: Hadi Valadi; Karin Ekström; Apostolos Bossios; Margareta Sjöstrand; James J Lee; Jan O Lötvall Journal: Nat Cell Biol Date: 2007-05-07 Impact factor: 28.824
Authors: Soudeh Ghafouri-Fard; Tayyebeh Khoshbakht; Bashdar Mahmud Hussen; Aria Baniahmad; Wojciech Branicki; Mohammad Taheri; Ahmad Eghbali Journal: Front Cell Dev Biol Date: 2022-07-05
Authors: Francesco Angelini; Francesca Pagano; Antonella Bordin; Vittorio Picchio; Elena De Falco; Isotta Chimenti Journal: Front Cardiovasc Med Date: 2017-10-06