Hydrogen peroxide alters signal transduction in human endothelial cells

Lytic H₂O₂-induced injury to human umbilical vein endothelial cells provides a model for endothelial cell damage in diverse states including acute respiratory distress and septic shock. Endothelial cell lysis is an extreme result of inflammatory cell activation. Functional alterations such as responsiveness to endothelial cell agonists and eicosanoid production might be impaired by exposure to inflammatory cell products including H₂O₂. Soluble mediators such as thrombin or histamine cause endothelial cell activation via a signal transduction mechanism that hydrolyzes phosphatidylinositol 4,5-bisphosphate (IP), liberating inositol trisphosphate (IP₃). Accordingly, pretreatment of endothelial cells with H₂O₂ blocked the subsequent production of IP₃ in response to thrombin and histamine. H₂O₂ inhibition of IP₃ was time- and concentration-dependent. The endothelial cells were viable by trypan blue dye exclusion and chromium release. H₂O₂ inhibition of signaling was completely prevented by catalase. Iron-dependent oxidant radical formation appears critical because deferoxamine (10^-4 mol/L) pretreatment of endothelial cells prevented H₂O₂ inhibition of IP hydrolysis. Prostacyclin and platelet activating factor production in response to thrombin have been linked to IP hydrolysis. Pretreatment of endothelial cells with H₂O₂ reduced prostacyclin and platelet-activating factor production by thrombin by at least 50%. It appears H₂O₂ can induce defects in signaling pathways with sequelae (decreased prostacyclin and platelet-activating factor) short of endothelial cell death. The possible consequences of H₂O₂ interaction with endothelial cells is reviewed with the aim of presenting a hypothesis to integrate these various observations.