Deng Shanming, Wang Huilan, Jia Chunling, Zhu Shoukang, Chu Xianming, Ma Qi, Wei Jianqin, Chen Emily, Zhu Wei, Macon Conrad J, Jayaweera Dushyantha T, Dykxhoorn Derek M, Dong Chunming
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.).
Arterioscler Thromb Vasc Biol. 2017 Feb;37(2):280-290. doi: 10.1161/ATVBAHA.116.308378. Epub 2016 Dec 1.
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.
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.
(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.
谱系阴性骨髓细胞（lin- BMCs）富含内皮祖细胞并介导血管修复。衰老相关的衰老和凋亡导致lin- BMCs数量减少和功能下降，损害其促修复能力。lin- BMCs衰老和凋亡的分子机制尚不清楚。微小RNA（miRNAs）调节许多重要的生物学过程。鉴定调节lin- BMCs健康和功能的miRNA-mRNA网络是理解血管修复过程的关键步骤。本研究的目的是表征miR-146a- Polo样激酶2（Plk2）网络在调节lin- BMCs衰老、凋亡及其血管生成能力中的作用。
对从年轻和老年野生型及载脂蛋白E（ApoE）小鼠分离的lin- BMCs进行转录组分析，结果显示miR-146a表达随年龄显著增加。通过计算机分析、表达研究和荧光素酶报告基因检测确定Plk2是miR-146a的直接靶标。年轻lin- BMCs中miR-146a过表达抑制Plk2表达，分别通过p16Ink4a/p19Arf和p53导致衰老和凋亡增加，以及体内外血管生成能力受损。相反，老年lin- BMCs中miR-146a的抑制增加了Plk2表达并使lin- BMCs恢复活力，导致衰老和凋亡减少，从而改善血管生成。
（1）miR-146a通过抑制Plk2表达来调节lin- BMCs的衰老和凋亡，而Plk2表达反过来激活p16Ink4a/p19Arf和p53；（2）调节miR-146a或其靶标Plk2可能代表一种潜在的治疗干预措施，以改善lin- BMCs介导的血管生成和血管修复。
