title: Oxidative stress mediates chemerin-induced autophagy in endothelial cells.
abstract: 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-α (AMPKα) 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 AMPKα. Analysis of the HAECs revealed that inhibition of autophagy by Mito-TEMPO or shRNA against ChemR23, AMPKα, 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.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology and Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People s Republic of China. wlshen@sibs.ac.cn
authors.forename: Weili
authors.initials: W
authors.lastname: Shen
authors.forename: Chuan
authors.initials: C
authors.lastname: Tian
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Dingliang
authors.initials: D
authors.lastname: Zhu
authors.forename: Pingjin
authors.initials: P
authors.lastname: Gao
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D001343:Autophagy; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000378:metabolism; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D017382:Reactive Oxygen Species