C-C motif ligand 8 promotes atherosclerosis via NADPH oxidase 2/reactive oxygen species-induced endothelial permeability increase.

Abstract

Chemokines have been reported to play important roles in atherosclerotic development. Recently, we found C-C motif ligand 8 (CCL8), a rarely studied chemokine in atherosclerosis, was highly expressed in the endothelium of advanced human carotid plaques. We hypothesized whether CCL8 promotes atherosclerosis through endothelial dysfunction. Apolipoprotein E-deficient mice under the Western diet were used to construct atherosclerosis models. Adeno-associated viruses (AAV) with CCL8 and the CCL8-antibody were injected into mice respectively to conduct CCL8 overexpression and suppression. The results showed that atherosclerotic lesions were significantly increased in the AAV-CCL8 group, while, lesions in the aortic sinus were reduced in the CCL8-antibody group. With CCL8 treatment (200 ng/ml, 24 h) in vitro, the permeability of human aortic endothelial cells (HAECs) increased and the expression of junctional proteins Zonula occluden-1, and Vascular endothelial cadherin were decreased. This effect was dependent on reactive oxygen species (ROS) generation, which could be blocked by l-Ascorbic acid and Apocynin. Results showed that NADPH oxidase 2 (NOX2) expression also increased with CCL8 stimulation and the ROS, and permeability increase of HAECs could be inhibited when NOX2 interfered with the specific siRNA. Additionally, we further found ERK1/2, PI3K-AKT, and NF-κB pathways were involved in the activation of CCL8. Our results indicated that CCL8 might also play important roles in atherosclerosis and this effect, at least in part, was caused by NOX2/ROS-induced endothelial permeability increase. This study might contribute to a deeper understanding of the connection between chemokines and atherosclerosis.

• Authors: Song Xue, Hanfei Tang, Gefei Zhao, Chao Fang, Yang Shen, Dong Yan, Ye Yuan, Weiguo Fu, Zhenyu Shi, Xiao Tang, Daqiao Guo
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 167 Pg. 181-192 (05 01 2021) ISSN: 1873-4596 [Electronic] United States
• PMID: 33741452 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Ccl8 protein, mouse
• Chemokine CCL8
• Ligands
• Reactive Oxygen Species
• NADPH Oxidase 2
• NADPH Oxidase 4
• NADPH Oxidases

Topics

• Animals
• Atherosclerosis (genetics)
• Cells, Cultured
• Chemokine CCL8
• Endothelial Cells
• Endothelium
• Ligands
• Mice
• NADPH Oxidase 2 (genetics)
• NADPH Oxidase 4
• NADPH Oxidases (genetics)
• Permeability
• Phosphatidylinositol 3-Kinases
• Reactive Oxygen Species