© 1998 American Heart Association, Inc.
Original Contributions |
Unsaturated Fatty Acids Increase Plasminogen Activator Inhibitor-1 Expression in Endothelial Cells
From the Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital (L.N., A.H., P.E.), and the Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Huddinge University Hospital, Karolinska Institute (U.D.), Stockholm, Sweden; and the Institute of Pharmacological Sciences, University of Milan (C.B., E.T.), Italy.
Correspondence to Per Eriksson, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail Per.Eriksson{at}medks.ki.se
Abstract—In vivo studies have demonstrated a strong positive correlation between plasma very low density lipoprotein (VLDL) triglyceride and plasma plasminogen activator inhibitor-1 (PAI-1) activity levels. Furthermore, VLDL has been shown to induce PAI-1 secretion from cultured endothelial cells. In contrast, no or variable effects on PAI-1 secretion have been reported for native low density lipoprotein. It could be speculated that fatty acids derived from VLDL triglycerides are the actual mediators, resulting in an enhanced secretion of PAI-1. In the present study, we have analyzed the effects of both saturated and unsaturated fatty acids on PAI-1 expression and secretion by endothelial cells. Addition of 0 to 50 µmol/L of either palmitic acid or stearic acid had no effect on PAI-1 secretion from human umbilical vein endothelial cells or EA.hy926 cells. In contrast, addition of oleic acid, linoleic acid, linolenic acid, and eicosapentaenoic acid resulted in a significant increase in PAI-1 secretion from both cell types. Northern blot analysis of PAI-1 mRNA levels was in agreement with these findings. Transfection experiments demonstrated that addition of linolenic acid and eicosapentaenoic acid significantly increased PAI-1 transcription. The fatty acid response region was localized to a previously described VLDL-inducible region of the PAI-1 promoter. Electromobility shift assays demonstrated that unsaturated fatty acids induced the same complex as did VLDL, whereas saturated fatty acids had no effect. Furthermore, it was demonstrated that the activation procedure did not involve fatty acid oxidation to any significant extent. In conclusion, the present study demonstrates that unsaturated fatty acids increase PAI-1 transcription and secretion by endothelial cells in vitro. The effect appears to be mediated by a previously described VLDL-inducible transcription factor.
Key Words: PAI-1 • fatty acids • promoter • endothelial cells • VLDL
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