Survivin regulated by autophagy mediates hyperglycemia-induced vascular endothelial cell dysfunction
Survivin regulated by autophagy mediates hyperglycemia-induced vascular endothelial cell dysfunction
复制标题
自噬调节的生存素介导高血糖诱导的血管内皮细胞功能障碍
DOI：
10.1016/j.yexcr.2018.01.037
复制
发表时间：
2018-03-15
影响因子：
3.7
通讯作者：
Yang, Shuyu
中科院分区：
文献类型：
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作者：
Xu, Yu-Xue;Huang, Caoxin;Yang, Shuyu
糖尿病血管并发症通常定义为血管内皮病变。然而，作为一种可塑性细胞类型，内皮细胞在高血糖刺激下是否会从静止状态转变为过度活跃状态并阻碍血管稳定性，以及这一过程是否参与了糖尿病血管并发症仍不清楚。Survivin是一种抗肿瘤细胞凋亡的蛋白质，它通过促进细胞增殖或抑制细胞凋亡而发挥作用。因此，本研究旨在探讨高血糖对内皮细胞状态的影响和生存素的潜在参与。我们发现，高葡萄糖（25 mM）不会引起内皮损伤，相反，它明显促进内皮细胞增殖和管形成能力，表明高血糖时内皮细胞功能障碍，其特征在于其偏好于高活性状态。同时，检测到生存素的上调伴随着自噬途径的关键组分升高，包括LC 3，Beclin 1和p62。Survivin的特异性抑制剂YM 155可抑制高血糖诱导的内皮细胞过度活化。自噬抑制剂（3 MA）和激动剂（雷帕霉素）的应用支持Survivin可能作为自噬的下游效应。因此，我们的研究结果表明，生存素/自噬轴是一个潜在的治疗糖尿病血管并发症的治疗靶点。
Diabetic vascular complications are often defined by vascular endothelial lesions. However, as a plastic cell type, whether endothelial cells could transit from quiescence to hyper-active status and hamper vascular stability upon hyperglycemia stimulation and whether this process is involved in diabetic vascular complications remain obscure. Survivin has been identified as an anti-apoptotic protein in tumor or epithelial cells by either promoting proliferation or inhibiting apoptosis. Therefore, this study aims at investigating the effects of hyperglycemia on endothelial cell status and the potential involvement of survivin. We found that high glucose (25 mM) did not cause endothelial injuries, instead, it evidently promotes endothelial proliferation and tube formation capacity indicating endothelial cell dysfunction upon hyperglycemia characterized by its preference to hyper-active status. Concomitantly, an upregulation of survivin was detected accompanied by the key component elevations of autophagy pathway including LC3, Beclin1, and p62. YM155, a specific inhibitor of survivin, could abrogate hyperglycemia-induced endothelial hyper-activation. Application of the autophagy inhibitor (3MA) and agonist (rapamycin) supported that survivin could be as a downstream effect or of autophagy. Thus, our results suggested that survivin/autophagy axis a potential therapeutic target in treatment of diabetic vascular complications.