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

Abstract

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. (Arterioscler Thromb Vasc Biol. 1999;19:1577-1581.)Key Words: PAI-1 Ⅲ fibrates Ⅲ endothelial cells Ⅲ transcriptional activity F ibrate compounds are widely used in the treatment of some forms of diet-resistant hyperlipidemia. The main effect consists of a profound lowering of the plasma concentrations of VLDL lipids and a moderate rise in HDL cholesterol. 1 In addition, fibrates have favorable effects on blood coagulation and global fibrinolytic function, which may be at least partly mediated by the lowering of plasma concentrations of triglyceride-rich lipoproteins. 1 The consistent positive correlation between triglyceride and plasminogen activator inhibitor-1 (PAI-1) levels in plasma 2 and the fact that VLDL induces secretion of PAI-1 from cultured human umbilical vein endothelial cells (HUVECs) 3-5 and human hepatoblastoma (HepG2) cells 4,6 have raised the question of whether fibrate treatment might improve fibrinolytic function by reducing the plasma levels of PAI-1, the fast-acting inhibitor of plasminogen activators and the principal regulator of the endogenous fibrinolytic enzyme system. This issue has now been addressed in a number of short-term, controlled clinical trials using various fibrate compounds. However, the results with respect to lowering of plasma PAI-1 activity have been discrepant: an overall significant effect, 7 a...

Oxidative stress modulates PPARγ in vascular endothelial cells

“…Additionally, PPARγ expression and activity were examined in BAECs after manipulating the extracellular thiol/disulfide E h of the Cys/CySS couple, which has been suggested to release intracellular H 2 O 2 [26, 40]. Our results show that prolonged H 2 O 2 exposure reduced HUVEC PPARγ mRNA levels but failed to alter HUVEC PPARγ activity, whereas acute H 2 O 2 treatment reduced PPARγ mRNA levels, activity, and the expression of two PPARγ-regulated genes, PAI-1 and PTEN [3, 18, 32]. Alterations in PPARγ expression were mediated by H 2 O 2 as they were inhibited by catalase and not reproduced by oxidized media components.…”

“…Compared with untreated HUVECs, H 2 O 2 significantly decreased HUVEC PPARγ activity levels 0.5 and 2 h following the onset of oxidative stress, whereas near complete recovery of PPARγ activity was observed 4 h following the onset of H 2 O 2 exposure (Figure 3C). To explore the biological function of PPARγ in H 2 O 2 -treated endothelial cells, PAI-1 and PTEN mRNA levels were examined as representative PPARγ-target genes in endothelial cells [3, 18, 32]. Treating HUVECs with H 2 O 2 for 2 h significantly decreased PAI-1 and PTEN mRNA levels in a time-dependent manner (Figure 3D and 3E, respectively).…”

Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR–α Activators

“…77 In cultured human endothelial cells, fenofibrate and gemfibrozil significantly decrease PAI-1 levels and may as such modulate the risk of thrombus formation. [77][78][79] In vivo evidence, however, is still controversial and further investigation is needed.…”

Fenofibrate: Metabolic and Pleiotropic Effects

“…However, studies of the effects of fibrates on PAI-1 synthesis in liver cells in culture were more conclusive [142]. Even though individual fibrates have diverse effects on PAI-1 expression in endothelial cells, fenofibrate and gemfibrozil markedly decreased PAI-1 transcription and secretion from endothelial cells [143]. Furthermore, Kaneko et al showed that fenofibric acid inhibited basic fibroblast growth factor-stimulated PAI-1 expression [144].…”