Oxidative stress mediates chemerin-induced autophagy in endothelial cells
Oxidative stress mediates chemerin-induced autophagy in endothelial cells
复制标题
氧化应激介导凯莫瑞诱导的内皮细胞自噬
DOI：
10.1016/j.freeradbiomed.2012.11.011
复制
发表时间：
2013-02-01
影响因子：
7.4
通讯作者：
Liu, Jiankang
中科院分区：
文献类型：
--
作者：
Shen, Weili;Tian, Chuan;Liu, Jiankang
Chmerin是一种与肥胖和代谢综合征相关的新型脂肪因子。以往的研究表明，趋化蛋白也可能作为血管生成的刺激因子发挥作用。然而，其调控血管生成的潜在机制在很大程度上仍不清楚。在这项研究中，我们确定了自噬在趋化蛋白诱导的血管生成中的作用。用趋化蛋白处理人主动脉内皮细胞(HAECs)可增加线粒体活性氧物种(ROS)的产生，同时诱导与自噬相关的基因Beclin-1、ATG7和Atg12-ATG5的表达，并随时间的变化而增加。通过shRNA或线粒体靶向抗氧化剂Mito-tembo抑制趋化蛋白受体23(ChemR23)，可减少趋化蛋白相关ROS的产生，并取消自噬相关基因的上调。此外，趋化蛋白处理HAEC可增加AMP激活的蛋白激酶-α(AMPKα)活性和乙酰辅酶A羧化，降低哺乳动物靶标雷帕霉素、核糖体蛋白S6激酶-1和真核细胞起始因子4E结合蛋白1的磷酸化，这些作用可被Mito-tembo或shRNA介导的AMPKα基因敲除所阻断。对HAEC的分析表明，Mito-tembo或针对ChemR23、AMPKα和Beclin-1的shRNA抑制自噬会削弱趋化蛋白诱导的管状形成和细胞增殖。这些研究表明，线粒体ROS在趋化蛋白诱导的血管生成中对自噬是重要的，靶向自噬可能为治疗心血管疾病提供一种重要的新工具。(C)2012 Elsevier Inc.保留所有权利。
Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Previous studies indicate that chemerin may also function as a stimulator of angiogenesis. However, the underlying mechanism of its regulatory role in angiogenesis remains largely unknown. In this study, we determined the role of autophagy in chemerin-induced angiogenesis. Treatment of human aorta endothelial cells (HAECs) with chemerin increased the generation of mitochondrial reactive oxygen species (ROS) concurrent with the induced, time-dependent expression of LC3II and upregulation of the autophagy-related genes beclin-1, Atg7, and Atg12-Atg5. Knockdown of chemerin receptor 23 (ChemR23) by shRNA or treatment with the mitochondria-targeted antioxidant Mito-TEMPO decreased the chemerin-associated ROS generation and abolished the upregulation of autophagy-related genes. Furthermore, chemerin treatment of HAECs augmented AMP-activated protein kinase-alpha (AMPK alpha) activity and acetyl-CoA carboxylase phosphorylation and reduced phosphorylation of the mammalian target of rapamycin, ribosomal protein S6 kinase-1, and eukaryotic initiation factor 4E-binding protein 1, which were blocked by coadministration of Mito-TEMPO or shRNA-mediated knockdown of AMPK alpha. Analysis of the HAECs revealed that inhibition of autophagy by Mito-TEMPO or shRNA against ChemR23, AMPK alpha, and beclin-1 impaired chemerin-induced tube formation and cell proliferation. These studies show that mitochondrial ROS are important for autophagy in chemerin-induced angiogenesis and that targeting autophagy may provide an important new tool for treating cardiovascular disease. (c) 2012 Elsevier Inc. All rights reserved.