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Cardiovasc Pharm Open Access. 2015 Apr;4(1). pii: 132. doi: 10.4172/2329-6607.1000132. Epub 2015 Feb 26.

A Novel ASK Inhibitor AGI-1067 Inhibits TLR-4-Mediated Activation of ASK1 by Preventing Dissociation of Thioredoxin from ASK1.

Author information

1
The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
2
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
3
Interdepartmental Program in Vascular Biology and Therapeutics, Dept. of Pathology, Yale University School of Medicine, New Haven, CT 06520.

Abstract

The cell type that normally limits the inflammatory and atherosclerotic process is the vascular endothelial cell (EC) that can be regulated by proinflammatory and various stresses. Toll-like receptor-4 (TLR4) plays an important role in the pathogenesis of atherosclerosis, in part, by activating apoptosis signal-regulating kinase 1 (ASK1) to initiate the activation of MAP kinases pathways and the expression of inflammatory genes. In the present study, we test the hypothesis that AGI-1067 acts as an anti-inflammatory agent by inhibiting the activation of ASK1 in human EC. Pretreatment of human aortic endothelial cells with AGI-1067 inhibits TLR4 ligand (LPS)-induced activation of ASK1 and the downstream p38 and c-Jun N-terminal kinase (JNK) MAP kinases. LPS dissociates two endogenous inhibitors thioredoxin-1 (Trx1) and 14-3-3 from ASK1, leading to ASK1 autoactivation. Interestingly, AGI-1067 inhibits the dissociation of Trx1, but not 14-3-3, from ASK1. However, inhibition of Trx1 dissociation from ASK1 by AGI-1067 is sufficient to suppress LPS-mediated phosphorylation of the transcription factors c-Jun and activating transcription factor 2, and inhibit LPS-induced inflammatory genes including vascular cell adhesion molecule 1, E-selectin, IL-6 and monocyte chemoattractant protein 1. Our findings suggest that AGI-1067 as a unique ASK1 inhibitor to inhibit TLR4-mediated ASK1 activation, contributing to its anti-inflammatory properties.

KEYWORDS:

AGI-1067; apoptosis signal-regulating kinase 1; mitogen-activated protein kinase; thioredoxin; toll-like receptor 4

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