Adiporedoxin suppresses endothelial activation via inhibiting MAPK and NF-κB signaling.

Hui He,Daping Fan,Fatma Saaoud,Susan Lessner,Michelle Fan,Brooks D Kimmis,Fang Guo,Christopher J Papasian,Jeena Sandhu,Zhisheng Jiang,Yong Li,Mingui Fu,Dev Maulik

doi:10.1038/srep38975

Abstract

Adiporedoxin (Adrx) is a recently discovered redox regulatory protein that is preferentially expressed in adipose tissue and plays a critical role in the regulation of metabolism via its modulation of adipocyte protein secretion. We here report that Adrx suppresses endothelial cell activation via inhibiting MAPK and NF-kB signaling pathways. Adrx is constitutively expressed in human vascular endothelial cells, and significantly induced by a variety of stimuli such as TNFα, IL-1β, H2O2 and OxLDL. Overexpression of Adrx significantly attenuated TNFα-induced expression of VCAM-1 and ICAM-1, and thus reduced monocyte adherence to human umbilical vein endothelial cells (HUVECs). Conversely, siRNA-mediated knockdown of Adrx increased TNFα-induced expression of adhesion molecules and monocyte adherence to HUVECs. Furthermore, forced expression of Adrx decreased TNFα-induced activation of ERK1/2, JNK, p38 and IKKs in HUVECs. Adrx mutant in the CXXC motif that lost its anti-redox activity is less efficient than the wild-type Adrx, suggesting that Adrx-mediated inhibition of endothelial activation is partially dependent on its antioxidant activity. Finally, Adrx expression was markedly increased in human atheroma compared with normal tissue from the same carotid arteries. These results suggest that Adrx is an endogenous inhibitor of endothelial activation, and might be a therapeutic target for vascular inflammatory diseases.

Highlights

Endothelial cell activation plays a key role in the pathogenesis of atherosclerosis and other vascular diseases[1]
To investigate the role of Adrx in vascular endothelial cells, we first examined the expression of Adrx in a variety of non- endotheial cell lines and compared them to endothelial cell lines, including human aortic endothelial cells (HAEC), human coronary artery endothelial cells (HCAEC), human dermal microvascular endothelial cells (HDMEC), human lung microvascular endothelial cells (HLMEC) and human umbilical vein endothelial cells (HUVECs)
We found that Adrx protein was enriched in all human endothelial cells except HCAECs

Summary

Introduction

Endothelial cell activation plays a key role in the pathogenesis of atherosclerosis and other vascular diseases[1]. A crucial step in chronic inflammation is the recruitment and transendothelial migration of monocytes from the circulation into the subendothelial space of large arteries, where they differentiate into macrophages and become functionally active[2] These processes are precisely controlled by cytokines such as interleukin-1β(IL-1β), IL-6, IL-8 and tumor necrosis factor α(TNFα), which stimulate endothelial cell expression of adhesion molecules and chemokines[3,4]. These latter molecules attract leukocytes to the vascular wall, promoting inflammation and atherogenesis[3]. The expression of Adrx is markedly increased in human atheroma, suggesting that Adrx may serve to suppress atherogenesis in humans

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Conclusion