Aldehydes mediate tissue factor induction: a possible mechanism linking lipid peroxidation to thrombotic events

Tissue factor (TF), which is expressed in atherosclerotic plaques and colocalizes with oxidized lipids, initiates the thrombogenic process. We have analyzed the effect of aldehydes derived from peroxidation of polyunsaturated fatty acids on TF expression in human vascular smooth muscle cells (HVSMC). Our results demonstrate that hexanal and 2,4-decadienal (2,4-DDE), two apolar aldehydes, increase TF expression. Exposure of HVSMC to hexanal for 2 h led to TF protein levels up to seven times higher than untreated cells whereas 2,4-DDE for 30 min led to them being up to 2.2 times higher. This induction of TF antigen by aldehydes correlates with an increase in TF mRNA levels. Electrophoretic mobility shift assays (EMSAs) showed that the binding activity of the transcription factor AP-1 (c-Fos/c-Jun) to TF promoter was elevated in response to these oxidation products. This enhancement was associated to an increase of c-fos transcriptional activity, which was reversible by pretreatment with simvastatin. We conclude that the induction of TF by aldehydes might contribute to the severity of atherogenesis.