SNHG9, delivered by adipocyte-derived exosomes, alleviates inflammation and apoptosis of endothelial cells through suppressing TRADD expression
SNHG9, delivered by adipocyte-derived exosomes, alleviates inflammation and apoptosis of endothelial cells through suppressing TRADD expression
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SNHG9 由脂肪细胞来源的外泌体递送，通过抑制 TRADD 表达减轻内皮细胞的炎症和凋亡
DOI：
10.1016/j.ejphar.2020.172977
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发表时间：
2020-04-05
影响因子：
5
通讯作者：
Feng, Chuanjie
中科院分区：
文献类型：
--
作者：
Song, Yanbin;Li, Hua;Feng, Chuanjie
外泌体是源自细胞膜的囊泡，通过与细胞膜融合将RNAs和蛋白质转移至靶细胞，在细胞信号传导中发挥关键作用。长链非编码RNA - 小核仁RNA宿主基因9（lncRNA - SNHG9）在脂肪细胞分化过程中被证明是lncRNA - mRNA相互作用网络中的一个重要元素，这表明它可能参与肥胖的发展，而肥胖是心脑血管内皮功能障碍的一个重要危险因素。然而，外泌体中的lncRNA - SNHG9在肥胖患者内皮功能障碍中的作用在很大程度上是未知的。在本研究中，我们证明了脂肪细胞衍生的外泌体SNHG9在肥胖者中表达下调，并且在伴有内皮功能障碍的肥胖个体中进一步降低。功能实验表明，脂肪细胞衍生的外泌体SNHG9减轻了内皮细胞的炎症和凋亡。生物信息学分析显示，SNHG9与肿瘤坏死因子受体1相关死亡结构域蛋白（TRADD）mRNA之间存在潜在的相互作用。然后，基于Ago2抗体的RNA结合蛋白免疫沉淀试验和核糖核酸酶保护试验表明，外泌体SNHG9直接与TRADD mRNA序列中的特定区域结合，并形成一个RNA二聚体诱导沉默复合物。此外，敲低TRADD显著抑制人脐静脉内皮细胞（HUVECs）的炎症和凋亡，而TRADD的过表达则显著抵消了外泌体SNHG9对上皮功能障碍的保护作用。因此，SNHG9可通过抑制炎症和凋亡来预防肥胖患者的内皮功能障碍，这表明SNHG9可能是伴有内皮功能障碍的肥胖患者的一个潜在治疗靶点。
Exosomes are membrane-derived vesicles and play a critical role in cell signaling by transferring RNAs and proteins to target cells through fusion with the cell membrane. Long non-coding RNA-small nucleolar RNA host gene 9 (lncRNA-SNHG9) was proven to be an important element in lncRNA-mRNA interaction networks during adipocyte differentiation, suggesting its potential involvement in the development of obesity, an important risk factor of cardiovascular and cerebrovascular endothelial dysfunction. However, the role of lncRNA-SNHG9 within the exosome in endothelial dysfunction of obese patients is largely unknown. In this study, we proved that adipocytes-derived exosomal SNHG9 were downregulated in obese persons and further decreased in obese individuals with endothelial dysfunction. Functional experimentations demonstrated that adipocytes-derived exosomal SNHG9 alleviated inflammation and apoptosis in endothelial cells. Bioinformatic analysis revealed that there was a potential interaction between SNHG9 and the TNF receptor type 1-associated death domain protein (TRADD) mRNA. Then, RNA-binding protein immunoprecipitation assay based on Ago2 antibody and ribonuclease protection assay demonstrated that exosomal SNHG9 directly bound to a specific region in TRADD mRNA sequence and formed an RNA dimeric inducible silencing complex. Moreover, knockdown of TRADD markedly inhibited inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs), whereas overexpression of TRADD dramatically neutralized the protective effect of exosomal SNHG9 on epithelial dysfunction. Therefore, SNHG9 could prevent endothelial dysfunction in obese patients by suppressing inflammation and apoptosis, indicating that SNHG9 may be a potential therapeutic target for obese patients with endothelial dysfunction.