National Center of Gerontology, Department of Vascular Surgery, Beijing Hospital , Beijing , People's Republic of China.
Beijing Neurosurgical Institute, Capital Medical University , Beijing , People's Republic of China.
Am J Physiol Cell Physiol. 2019 Jun 1;316(6):C830-C843. doi: 10.1152/ajpcell.00262.2018. Epub 2018 Dec 21.
Long noncoding RNAs (lncRNAs) are commonly associated with various biological functions, in which the function of lncRNA maternally expressed gene 3 (MEG3) has been identified in various cancers. Strikingly, an association between MEG3 with microRNAs (miRNAs), mRNAs, and proteins has been reported. This study investigates the role of MEG3 in vascular endothelial cell (VEC) senescence. Expression of Girdin and miR-128 was monitored in the blood vessel samples of young and old mice/healthy volunteers, along with the measurement of human umbilical vein endothelial cells (HUVECs). The relationship between MEG3/Girdin and miR-128 was determined and verified. Loss- and gain-of-function approaches were applied to analyze the regulatory effects of MEG3 on platelet phagocytosis and lipoprotein oxidation of HUVEC membrane. In addition, the effect of MEG3 on HUVEC senescence was evaluated by detection of the reactive oxygen species, telomerase activity, and telomere length. To further analyze the MEG3-mediated regulatory mechanism, miR-128 upregulation and inhibition were introduced into the HUVECs. Downregulated Girdin and upregulated miR-128 were found in the blood vessels of old individuals and old mice, as well as in senescent HUVECs. MEG3 downregulation was found to be capable of inhibiting Girdin but enhancing miR-128 expression. It was also indicated to inhibit platelet phagocytosis and reduce telomerase activity and telomere length, while enhancing lipoprotein oxidation and reactive oxygen species production, which ultimately contributed in preventing and protecting HUEVCs from senescence. These findings provide evidence supporting that MEG3 leads to miR-128 downregulation and Girdin upregulation, which promotes platelet phagocytosis, thus protecting VECs from senescence.
长链非编码 RNA（lncRNA）通常与各种生物学功能相关，其中 lncRNA 母系表达基因 3（MEG3）的功能已在各种癌症中得到鉴定。引人注目的是，已经报道了 MEG3 与 microRNAs（miRNAs）、mRNAs 和蛋白质之间的关联。本研究调查了 MEG3 在血管内皮细胞（VEC）衰老中的作用。监测了年轻和年老小鼠/健康志愿者的血管样本中的 Girdin 和 miR-128 的表达，以及人脐静脉内皮细胞（HUVEC）的测量。确定并验证了 MEG3/Girdin 和 miR-128 之间的关系。应用缺失和获得功能方法来分析 MEG3 对 HUVEC 膜血小板吞噬和脂蛋白氧化的调节作用。此外，通过检测活性氧、端粒酶活性和端粒长度来评估 MEG3 对 HUVEC 衰老的影响。为了进一步分析 MEG3 介导的调节机制，引入了 miR-128 的上调和抑制作用。在个体衰老和年老的小鼠血管中以及衰老的 HUVEC 中发现下调的 Girdin 和上调的 miR-128。下调 MEG3 被发现能够抑制 Girdin 但增强 miR-128 的表达。它还被表明能够抑制血小板吞噬并降低端粒酶活性和端粒长度，同时增强脂蛋白氧化和活性氧的产生，这最终有助于预防和保护 HUEVC 免受衰老。这些发现为 MEG3 导致 miR-128 下调和 Girdin 上调，从而促进血小板吞噬，从而保护 VEC 免受衰老提供了证据。
