Pterostilbene, a natural small-molecular compound, promotes cytoprotective macroautophagy in vascular endothelial cells
Pterostilbene, a natural small-molecular compound, promotes cytoprotective macroautophagy in vascular endothelial cells
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DOI：
10.1016/j.jnutbio.2012.06.008
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发表时间：
2013-05-01
影响因子：
5.6
通讯作者：
Sun, WenKai
中科院分区：
文献类型：
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作者：
Zhang, Lu;Cui, LiuQing;Sun, WenKai
自噬的化学调节剂由于其在疾病治疗中的潜力而引起了生物学家和临床医生的广泛兴趣。紫檀芪（PT）是一种天然小分子化合物，具有抑制氧化低密度脂蛋白（oxLDL）诱导的血管内皮细胞凋亡的作用。本研究的目的是研究PT是否以及如何诱导VEC自噬。0.5或1 μ M的PT可有效诱导人脐静脉内皮细胞（HUVECs）自噬体的形成。PT通过细胞内钙（[Ca 2 +]（i））浓度的快速升高和随后的AMP活化蛋白激酶α 1亚基（AMPK α 1）活化促进自噬，这反过来又抑制了雷帕霉素（一种有效的自噬抑制剂）的哺乳动物靶标。PT诱导的AMPK α 1激活和自噬对丝氨酸/苏氨酸激酶11的耗竭是难治的，但依赖于钙/钙调蛋白依赖性蛋白激酶β激活。有趣的是，PT刺激细胞保护性自噬，以帮助清除累积的毒性oxLDL并抑制HUVECs的凋亡。我们的研究提供了一个有效的小分子自噬增强剂和一个新的有用的工具，在探索细胞凋亡和自噬之间的串扰的分子机制。PT有望成为开发一类自噬调节剂的先导化合物，用于治疗自噬相关疾病。(C)2013 Elsevier Inc. All rights reserved.
Chemical modulators of macroautophagy (herein referred to as autophagy) have aroused widespread interest among biologists and clinical physicians because of their potential for disease therapy. Pterostilbene (PT), a natural small-molecular compound, has been demonstrated to inhibit oxidized low-density lipoprotein (oxLDL)-induced apoptosis in vascular endothelial cells (VECs). The aim of the present study was to investigate whether and how PT could induce VEC autophagy. PT at 0.5 or 1 mu M could effectively induce autophagosome formation in human umbilical vein VECs (HUVECs). PT promoted autophagy via a rapid elevation in intracellular calcium ([Ca2+](i)) concentration and subsequent AMP-activated protein kinase alpha 1 subunit (AMPK alpha 1) activation, which in turn inhibited mammalian target of rapamycin, a potent inhibitor of autophagy. PT-induced AMPK alpha 1 activation and autophagy were refractory to the depletion of serine/threonine kinase 11 but depended on calcium/calmodulin-dependent protein kinase-beta activation. Interestingly, PT stimulated cytoprotective autophagy so as to aid in the removal of accumulated toxic oxLDL and inhibit apoptosis in HUVECs. Our study provides a potent small molecule enhancer of autophagy and a novel useful tool in exploring the molecular mechanisms for crosstalk between apoptosis and autophagy. PT could serve as a potential lead compound for developing a class of autophagy regulator as autophagy-related diseases therapy. (C) 2013 Elsevier Inc. All rights reserved.