A Novel Class of Antioxidants Inhibit LPS Induction of Tissue Factor by Selective Inhibition of the Activation of ASK1 and MAP Kinases

Abstract

Objective-Oxidative stress contributes to the pathogenesis of many diseases, including atherosclerosis and sepsis. We have previously described a novel class of therapeutic compounds with antioxidant and antiinflammatory properties. However, at present, the intracellular targets of these compounds have not been identified. The purpose of this study was to elucidate the mechanism by which 2 structurally-related antioxidants (AGI-1067 and AGI-1095) inhibit LPS induction of tissue factor (TF) expression in human monocytic cells and endothelial cells. Methods and Results-We found that succinobucol (AGI-1067) and AGI-1095 inhibited LPS induction of TF expression in both monocytic cells and endothelial cells. These compounds also reduced LPS induction of nuclear AP-1 and expression of Egr-1 without affecting nuclear translocation of NF-B. Importantly, these antioxidants inhibited LPS activation of the redox-sensitive kinase, apoptosis signal-regulating kinase-1 (ASK1) and the mitogen-activated protein kinases (MAPKs) p38, ERK1/2, and JNK1/2. Conclusions-AGI-1067 and AGI-1095 inhibit TF gene expression in both monocytic cells and endothelial cells through a mechanism that involves the inhibition of the redox-sensitive MAP3K, ASK1. These compounds selectively reduce the activation/induction of MAPK, AP-1, and Egr-1 without affecting NF-B nuclear translocation. (Arterioscler Thromb

Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates lipopolysaccharide-induced tissue factor expression in pulmonary microvasculature

“…3). A recent study showed that radical scavenging activities of probucol derivatives attenuated that LPS induced ASK1 phosphorylation and TF expression in monocytic and endothelial cells [33]. These results support our conclusion that ASK1 plays an important role in LPS-induced TF expression in the vasculature.…”

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

“…Activation of MAP kinases mediates TF expression in response to many stimuli [18,25,28,30]. Guggulsterone impaired endothelial TF expression by specifically decreasing phosphorylation of JNK and p38, but not ERK, and consistent with MAP kinase inhibition, guggulsterone promoted a strong reduction in TNF-a-induced TF mRNA.…”

Dietary α-Linolenic Acid Inhibits Arterial Thrombus Formation, Tissue Factor Expression, and Platelet Activation

“…TNF-␣-induced endothelial TF expression is mediated through activation of MAP kinases leading to activation of transcription factors such as activator protein-1 and early growth response factor-1, whereas the IB kinase pathway promotes NF-B activation. 35,36 ASK1 is a redox-regulated kinase playing an essential role in stressinduced activation of MAP kinases, thus triggering various cellular processes, including inflammatory responses and TF expression. 32,37 In endothelial cells, TNF-␣ has been shown to activate ASK1, as well as MAP kinases.…”