Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells

The consistent positive correlation between triglyceride and plasminogen ac tivator inhibitor-1 (PAI-1) levels in plasma and the fact that very low den sity lipoprotein (VLDL) induces secretion of PAI-1 from cultured human umbi lical vein endothelial cells (HUVECs) and human hepatoblastoma cells have r aised the question of whether fibrate treatment, the main effect of which i s a profound lowering of plasma concentrations of VLDL, might improve fibri nolytic function by reducing the plasma levels of PAI-1. However, the findi ngs of controlled clinical trials using various fibrate compounds have been discrepant. ECs express PAI-1 under normal conditions in humans. We theref ore examined the effects of several fibrate compounds on PAI-1 expression a nd secretion by cultured HUVECs and the HUVEC-derived cell line EA.hy926. A ll fibrate compounds examined had significant effects on PAI-1 gene transcr iption in the EA.hy926 cells, Low concentrations of clofibric acid and beza fibrate increased PAI-1 transcription and secretion, whereas Wy-14643 incre ased PAI-1 synthesis in a dose-dependent way. In contrast, both fenofibric acid and gemfibrozil markedly decreased PAI-1 transcription and secretion f rom HUVECs and EA.hy926 cells. Thus, stimulation of the transcriptional act ivity of the PAI-1 gene by some fibrates is linked to increased secretion o f PAI-1 protein by the cells, whereas the opposite effects occur with other fibrate compounds. Whether the different effects on PAI-1 transcription an d secretion by ECs in vitro also reflect differences in treatment effects o n the regulation of plasma PAI-1 activity in vivo will have to be determine d in larger-scale, controlled clinical trials.