A novel class of antioxidants inhibit LPS induction of tissue factor by selective inhibition of the activation of ASK1 and MAP kinases.
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.


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-kappaB. 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-kappaB nuclear translocation.
Luyendyk
James P
JP
Department of Immunology, e Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Piper
J Daniel
JD
Tencati
Michael
M
Reddy
K Veera
KV
Holscher
Todd
T
Zhang
Rong
R
Luchoomun
Jayraz
J
Chen
Xilin
X
Min
Wang
W
Kunsch
Charles
C
Mackman
Nigel
N
D000975:Antioxidants / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002450:Cell Communication; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048848:MAP Kinase Kinase Kinase 5 / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism*
D000975:Antioxidants; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013925:Thromboplastin; D019950:Mitogen-Activated Protein Kinase 1; D048848:MAP Kinase Kinase Kinase 5