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.
Cabré
Anna
A
Unitat de Recerca de Lípids i Arteriosclerosi-Fundació IRCIS, Facultat de Medicina, Universitat Rovira i Virgili, Reus, Spain.
Girona
Josefa
J
Vallvé
Joan-C
JC
Masana
Lluís
L
D000447:Aldehydes / Q000032:analysis / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D016762:Genes, fos / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000096:biosynthesis / Q000187:drug effects*; D013927:Thrombosis / Q000503:physiopathology*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism
D000447:Aldehydes; D018808:Transcription Factor AP-1; D013925:Thromboplastin