4-Hydroxynonenal triggers Ca2+ influx in isolated rat hepatocytes.

Abstract Addition of micromolar concentrations of 4-hydroxynonenal (4-HNE), a reactive end-product of lipid peroxidation, to isolated rat hepatocytes was found to cause an early and transient increase in cytosolic Ca 2+ concentration followed by a more pronounced and progressive elevation. Such a late effect of 4-HNE was prevented by chelation of extracellular Ca 2+ with EGTA or by the addition of GdCl 3 , which is known to block the activity of store operated Ca 2+ channels in the hepatocyte plasma membrane. Moreover, the preincubation of isolated hepatocytes with the phospholipase C inhibitor U73122 resulted in a complete inhibition of both the early increase of cytosolic Ca 2+ and the subsequent Ca 2+ inflow. When 4-HNE was added to the hepatocytes 5 min after the empting of intracellular Ca 2+ pools by thapsigargin, the aldehyde caused a further increase in the accumulation of Ca 2+ which was prevented in the presence of GdCl 3 . Taken together these results indicate that in hepatocytes 4-HNE causes Ca 2+ inflow across GdCl 3 -sensitive Ca 2+ channels. The mechanism responsible for such an effect is triggered by the emptying of intracellular Ca 2+ pools likely resulting from 4-HNE mediated stimulation of phospholypase C, but 4-HNE also appears to interfere with the channel protein(s) or with the mechanism(s) regulating capacitative Ca 2+ inflow.