Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway
Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway
复制标题
白藜芦醇通过 cAMP 信号通路诱导自噬减轻血管内皮炎症
DOI：
10.4161/auto.26336
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发表时间：
2013-12-01
期刊：
影响因子：
13.3
通讯作者：
Mi, Man-tian
中科院分区：
文献类型：
--
作者：
Chen, Ming-liang;Yi, Long;Mi, Man-tian
炎症主要参与动脉粥样硬化（AS）的各个阶段，其开始于内皮的炎症变化，其特征在于粘附分子的表达。白藜芦醇（RSV）是一种天然存在的植物抗毒素，可以减轻内皮炎症，但其确切机制尚未完全阐明。自噬是指蛋白质和细胞器的细胞降解的正常过程，并且对某些炎性损伤具有保护作用。因此，我们打算确定自噬在RSV对人脐静脉内皮细胞（HUVECs）的抑制作用中的作用。我们发现RSV预处理以浓度依赖性方式减少肿瘤坏死因子α（TNF/TNFα）诱导的炎症，并增加MAP 1 LC 3B 2（微管相关蛋白1轻链3 β 2）表达和SQSTM 1/p62（隔离体1）降解。巴弗洛霉素A1（BafA 1）的挑战导致进一步积累的MAP 1 LC 3B 2在HUVEC。此外，自噬抑制剂3-甲基腺嘌呤（3-MA），氯喹以及ATG 5和BECN 1 siRNA显着减弱RSV诱导的自噬，这随后抑制了RSV诱导的炎症因子表达的下调。RSV还增加cAMP（环磷酸腺苷）含量、PRKA（蛋白激酶A）和SIRT 1（沉默调节蛋白1）的表达以及AMPK（AMP活化蛋白激酶）的活性。在ADCY（腺苷酸环化酶，KH 7）、PRKA（H-89）、AMPK（化合物C）或SIRT 1（烟酰胺和EX-527）的抑制剂以及ADCY、PRKA、AMPK和SIRT 1 siRNA转染的存在下，RSV诱导的HUVEC中的自噬被消除，表明RSV对自噬诱导的作用依赖于cAMP、PRKA、AMPK和SIRT 1。总之，RSV通过诱导自噬来减轻内皮炎症，并且自噬部分地通过cAMP-PRKA-AMPK-SIRT 1信号通路的激活来介导。
Inflammation participates centrally in all stages of atherosclerosis (AS), which begins with inflammatory changes in the endothelium, characterized by expression of the adhesion molecules. Resveratrol (RSV) is a naturally occurring phytoalexin that can attenuate endothelial inflammation; however, the exact mechanisms have not been thoroughly elucidated. Autophagy refers to the normal process of cell degradation of proteins and organelles, and is protective against certain inflammatory injuries. Thus, we intended to determine the role of autophagy in the antiinflammatory effects of RSV in human umbilical vein endothelial cells (HUVECs). We found that RSV pretreatment reduced tumor necrosis factor α (TNF/TNFα)-induced inflammation and increased MAP1LC3B2 (microtubule-associated protein 1 light chain 3 β 2) expression and SQSTM1/p62 (sequestosome 1) degradation in a concentration-dependent manner. A bafilomycin A1 (BafA1) challenge resulted in further accumulation of MAP1LC3B2 in HUVECs. Furthermore, autophagy inhibitors 3-methyladenine (3-MA), chloroquine as well as ATG5 and BECN1 siRNA significantly attenuated RSV-induced autophagy, which, subsequently, suppressed the downregulation of RSV-induced inflammatory factors expression. RSV also increased cAMP (cyclic adenosine monophosphate) content, the expression of PRKA (protein kinase A) and SIRT1 (sirtuin 1), as well as the activity of AMPK (AMP-activated protein kinase). RSV-induced autophagy in HUVECs was abolished in the presence of inhibitors of ADCY (adenylyl cyclase, KH7), PRKA (H-89), AMPK (compound C), or SIRT1 (nicotinamide and EX-527), as well as ADCY, PRKA, AMPK, and SIRT1 siRNA transfection, indicating that the effects of RSV on autophagy induction were dependent on cAMP, PRKA, AMPK and SIRT1. In conclusion, RSV attenuates endothelial inflammation by inducing autophagy, and the autophagy in part was mediated through the activation of the cAMP-PRKA-AMPK-SIRT1 signaling pathway.