Charles Kunsch

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. 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-&kgr;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-&kgr;B nuclear translocation.

Oxidation-Sensitive Transcription and Gene Expression in Atherosclerosis

Historically, most research into the role of oxidative stress and reactive oxygen species (ROS) in inflammatory diseases such as rheumatoid arthritis, pulmonary emphysema, neurodegenerative disorders and atherosclerosis has focused on the putative role of ROS as cellular damaging agents through the potential toxic oxidative modification of macromolecules such as proteins, lipids and DNA and on the cytotoxicity of free radicals and their reaction products (1). In this context, ROS have been viewed as playing a destructive role in biology. Although this may be true for high concentrations of ROS, many cell types such as fibroblasts, endothelial cells and smooth muscle cells have been shown to produce ROS at relatively low levels where they play a role as intracellular messenger molecules. In this context, ROS serve as physiological second messengers to regulate signal transduction pathways that ultimately control gene expression and post-translational modifications of proteins.