Oxidized lipoprotein regulation of tissue factor in smooth muscle cells

Abstract

Cell surface tissue factor (TF), which can initiate local coagulation, is upregulated in cells within atherosclerotic plaques, including macrophages, endothelial cells (EC) and smooth muscle cells (SMC). TF binds coagulation factors VIIa and Xa to make a catalytically active complex that produces thrombin and ultimately fibrin, leading to inflammation and coagulation. Using rat SMC, we have shown that lipids of low-density lipoprotein (LDL) and oxidized LDL (oxLDL) differentially regulate TF gene expression and TF activity. Unknown lipids of LDL induced the gene, but did not enhance activity. In contrast, oxLDL or its extracted lipids induced both the TF gene and TF activity. Specific lipids of oxLDL, e.g., lipid hydroperoxides, and H 2O 2 increased TF activity without enhancing TF gene or protein. The effects of lipid hydroperoxides were antioxidant-inhibitable. Lysophosphatidic acid (lysoPA) and lysophosphatidylcholine (lysoPC), important lipid mediators of many cellular processes and formed during LDL oxidation, increased TF mRNA, protein and activity. LysoPA induced the TF gene via a Gi-protein-coupled signaling process. Thus, different lipoprotein-borne lipids in atherosclerotic lesions enhance TF gene expression and TF activity through distinct mechanisms. These effects may contribute to lesion development and subsequent complications.