Dithiocarbamates: effects on lipid hydroperoxides and vascular inflammatory gene expression

Dithiocarbamates are a well-defined family of antioxidants that may have therapeutic uses such as in treatment of inflammation and atherosclerosis. A critical event in the pathogenesis of atherosclerosis is the infiltration of inflammatory cells into the vessel wall. Vascular cell adhesion molecule-1 (VCAM-1) plays a pivotal role in this process by mediating leukocyte binding to endothelial cells. VCAM-1 expression is stimulated by oxidized polyunsaturated fatty acids such as 13-hydroperoxy-octadecadienoic acid (13-HPODE), and this lipid hydroperoxide has been proposed to be a second messenger for induction of VCAM-1 gene expression. Pyrrolidine dithiocarbamate (PDTC) markedly represses cytokine-induced VCAM-1 gene expression in cultured human endothelial cells; however, its effects on the oxidative second messenger pathway are unknown. Using a lipoxygenase (LO) inhibition assay in tandem with a colorimetric assay for lipid peroxides, we determined that PDTC does not inhibit the enzymatic oxidation of linoleic acid to 13-HPODE by LO, but directly interacts with and chemically reduces 13-HPODE. We hypothesize that dithiocarbamates may intercept the oxidative second-messenger-induced expression of VCAM-1 and other redox-regulated genes important in inflammation and atherosclerosis.