OXIDATIVE MODIFICATION ENHANCES LIPOPROTEIN(A)-INDUCED OVERPRODUCTIONOF PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN CULTURED VASCULAR ENDOTHELIAL-CELLS

Elevated levels of plasma lipoprotein (a) [Lp(a)] have been considered as a strong risk factor for premature cardiovascular diseases. Plasmi nogen activator inhibitor-1 (PAI-1) is the major physiological inhibit or of plasminogen activators (PA). Increases in PAI-1 levels with or w ithout a reduction in PA levels have been frequently found in coronary artery disease patients. The present paper examined the effects of ox idized Lp(a) on the production of PAI-1 in cultured human umbilical ve in endothelial cells (HUVEC). Lp(a) and Lp(a)-free, low density lipopr otein (LDL) were prepared using lysine-Sepharose 4B affinity chromatog raphy. Incubations with 10(-8) M levels of native Lp(a) moderately inc reased the levels of biologically active PAI-1 in post-culture medium of HUVEC compared to that with equimolar concentrations of native Lp(a )-free LDL. The release of PAI-1 induced by Lp(a) was enhanced by oxid ative modification with copper ion. The stimulation of oxidized Lp(a) on PAI-1 production reached plateau in EC treated with 10-20 nM oxidiz ed Lp(a) modified by 5 mu M CuSO4. Treatment with 0.2 mu g/ml of actin omycin D significantly reduced native and oxidized Lp(a)-induced PAI-1 overproduction in EC. Increases in the steady state levels of PAI-1 m RNA were detected in native or oxidized Lp(a)-treated EC. The effect o f Lp(a)-free oxidized LDL on PAI-1 production was significantly weaker than the equimolar amount of oxidized Lp(a) but stronger than that of native LDL. Treatments with oxidized Lp(a) increased cell-associated PAI-1 to a similar extent as that in native Lp(a)-treated EC. The resu lts of the present paper demonstrate that oxidative modification enhan ces Lp(a)-induced PAI-1 production in vascular endothelial cells at RN A transcription level, which suggests that oxidization potentially amp lifies the anti-fibrinolytic and thrombotic effect of Lp(a). Copyright (C) 1997 Elsevier Science Ireland Ltd.