S17834, a new inhibitor of cell adhesion and atherosclerosis that targets NADPH oxidase

Oxidant stress is involved in the events that accompany endothelial cell ex pression of adhesion molecules and leukocyte adherence in many disease stat es, including atherosclerosis. A recently discovered benzo(b)pyran-4-one de rivative, S17834 (10 to 50 mu mol/L), reduced tumor necrosis factor-stimula ted vascular cell adhesion molecule-1 (VCAM) mRNA accumulation and protein expression in human umbilical vein endothelial cells. Intercellular cell ad hesion molecule-1 and E-selectin were also inhibited by S17834, but platele t endothelial cell adhesion molecule-1 was not. Adherence of U937 monocytic cells to the endothelial cells as well as to plastic plates coated with so luble VCAM, intercellular cell adhesion molecule-1, P-selectin, and E-selec tin was also decreased. Consistent with an antioxidant mechanism of action, S17834 (10 to 50 mu mol/L) inhibited tumor necrosis factor-stimulated rele ase of superoxide from endothelial cells measured by cytochrome c reduction . S17834 had no effect on superoxide produced by xanthine oxidase, indicati ng that rather than by acting as a scavenger of superoxide anion, the drug acts by inhibiting the production of free radicals. Indeed, S17834 inhibite d NADPH oxidase activity of endothelial cell membranes. The ability to inhi bit superoxide anion production appears to be key in the effect of S17834 o n superoxide anion production and VCAM expression, because these actions we re mimicked by adenovirus-mediated overexpression of superoxide dismutase. Furthermore, these actions may be relevant in vivo, because S17834 reduced aortic superoxide anion levels by 40% and aortic atherosclerotic lesions by 60% in apolipoprotein E-deficient mice. These results indicate that S17834 inhibits adhesion molecule expression and adherence of leukocytes to endot helial cells as well as aortic atherogenesis and that perhaps these effects can be explained by its ability to inhibit endogenous superoxide anion pro duction.