Glutathione peroxidase mimics prevent TNFα- and neutrophil-induced endothelial alterations

Based on the assumption that glutathione peroxidase (GPx) activity might be limiting in preventing peroxide-induced impairment of endothelial regulatory functions, we studied the effect of a series of new selenium-containing GPx mimics on endothelial cells exposed to an inflammatory stress. The two compounds that have the highest GPx activity, BXT-51072 and BXT-51077, were shown to be the most efficient inhibitors of leukocyte recruitment by human umbilical vein endothelial cells (HUVEC), upon incubation with neutrophils (10-fold excess over HUVEC) and with 1 ng/ml TNF-alpha for 1 or 3.5 h. When HUVEC were pre- and cotreated with 10 mu M of either compound, neutrophil adhesion and endothelial alteration were markedly inhibited, as assessed by immunoassays of myeloperoxidase and von Willebrand factor, respectively. These two GPx mimics were also found to be the most efficient inhibitors of the TNF alpha-induced endothelial expression of P- and E-selectin and of the TNF alpha- or interleukin 1-induced endothelial release of interleukin-8. Our results demonstrate that GPx mimics such as BXT-51072 behave as potent antagonists of TNF-cu and interleukin-l through the downregulation of endothelial proinflammatory responses. (C) 1998 Elsevier Science Inc.