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2015 ; 4
(1
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
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English Wikipedia
A Novel ASK Inhibitor AGI-1067 Inhibits TLR-4-Mediated Activation of ASK1 by
Preventing Dissociation of Thioredoxin from ASK1
#MMPMID28435845
Zheng S
; Long L
; Li Y
; Xu Y
; Jiqin Z
; Ji W
; Min W
Cardiovasc Pharm Open Access
2015[Apr]; 4
(1
): ä PMID28435845
show ga
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.