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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1577-1581.)
© 1999 American Heart Association, Inc.

Thrombosis

Effects of Fibrate Compounds on Expression of Plasminogen Activator Inhibitor-1 by Cultured Endothelial Cells

Lennart Nilsson; Toshiya Takemura; Per Eriksson; Anders Hamsten

From the Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.

Correspondence to Lennart Nilsson, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail lennart{at}instmed.ks.se

Abstract—The consistent positive correlation between triglyceride and plasminogen activator inhibitor-1 (PAI-1) levels in plasma and the fact that very low density lipoprotein (VLDL) induces secretion of PAI-1 from cultured human umbilical vein endothelial cells (HUVECs) and human hepatoblastoma cells have raised the question of whether fibrate treatment, the main effect of which is a profound lowering of plasma concentrations of VLDL, might improve fibrinolytic function by reducing the plasma levels of PAI-1. However, the findings of controlled clinical trials using various fibrate compounds have been discrepant. ECs express PAI-1 under normal conditions in humans. We therefore examined the effects of several fibrate compounds on PAI-1 expression and secretion by cultured HUVECs and the HUVEC-derived cell line EA.hy926. All fibrate compounds examined had significant effects on PAI-1 gene transcription in the EA.hy926 cells. Low concentrations of clofibric acid and bezafibrate increased PAI-1 transcription and secretion, whereas Wy-14643 increased PAI-1 synthesis in a dose-dependent way. In contrast, both fenofibric acid and gemfibrozil markedly decreased PAI-1 transcription and secretion from HUVECs and EA.hy926 cells. Thus, stimulation of the transcriptional activity of the PAI-1 gene by some fibrates is linked to increased secretion of PAI-1 protein by the cells, whereas the opposite effects occur with other fibrate compounds. Whether the different effects on PAI-1 transcription and secretion by ECs in vitro also reflect differences in treatment effects on the regulation of plasma PAI-1 activity in vivo will have to be determined in larger-scale, controlled clinical trials.

Key Words: PAI-1 • fibrates • endothelial cells • transcriptional activity

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