MicroRNA-146a induces lineage-negative bone marrow cell apoptosis and senescence by targeting polo-like kinase 2 expression

Shanming Deng, Huilan Wang, Chunling Jia, Shoukang Zhu, Xianming Chu, Qi Ma, Jianqin Wei, Emily Chen, Wei Zhu, Conrad J. Macon, Dushyantha T. Jayaweera, Derek M. Dykxhoorn, Chunming Dong

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)280-290
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume37
Issue number2
DOIs
StatePublished - Feb 1 2017

Keywords

  • apoptosis
  • cardiovascular diseases
  • mice
  • microRNAs
  • progenitor cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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