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.