UNSATURATED FATTY-ACIDS INCREASE PLASMINOGEN-ACTIVATOR INHIBITOR-1 EXPRESSION IN ENDOTHELIAL-CELLS

In vivo studies have demonstrated a strong positive correlation betwee n plasma very low density lipoprotein (VLDL) triglyceride and plasma p lasminogen activator inhibitor-1 (PAI-1) activity levels. Furthermore, VLDL has been shown to induce PAI-1 secretion from cultured endotheli al cells. In contrast, no or variable effects on PAI-I secretion have been reported for native low density lipoprotein. It could be speculat ed that fatty acids derived from VLDL triglycerides are the actual med iators, resulting in an enhanced secretion of PAI-1. In the present st udy, we have analyzed the effects of both saturated and unsaturated fa tty acids on PAT-1 expression and secretion by endothelial cells. Addi tion of 0 to 50 mu mol/L of either palmitic acid or stearic acid had n o effect on PAI-1 secretion from human umbilical vein endothelial cell s or EA.hy926 cells. In contrast, addition of oleic acid, linoleic aci d, linolenic acid, and eicosapentaenoic acid resulted in a significant increase in PAI-1 secretion from both cell types. Northern blot analy sis of PAI-1 mRNA levels was in agreement with these findings. Transfe ction experiments demonstrated that addition of linolenic acid and eic osapentaenoic acid significantly increased PAT-1 transcription. The fa tty acid response region was localized to a previously described VLDL- inducible region of the PAI-1 promoter. Electromobility shift assays d emonstrated that unsaturated fatty acids induced the same complex as d id VLDL, whereas saturated fatty acids had no effect. Furthermore, it was demonstrated that the activation procedure did not involve fatty a cid oxidation to any significant extent. In conclusion, the present st udy demonstrates that unsaturated fatty acids increase PAI-I transcrip tion and secretion by endothelial cells in vitro. The effect appears t o be mediated by a previously described VLDL-inducible transcription f actor.