Oxidative modification enhances lipoprotein(a)-induced overproduction of plasminogen activator inhibitor-1 in cultured vascular endothelial cells

Atherosclerosis. 1997 Jan 3;128(1):1-10. doi: 10.1016/s0021-9150(96)05971-0.

Abstract

Elevated levels of plasma lipoprotein (a) [Lp(a)] have been considered as a strong risk factor for premature cardiovascular diseases. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators (PA). Increases in PAI-1 levels with or without a reduction in PA levels have been frequently found in coronary artery disease patients. The present paper examined the effects of oxidized Lp(a) on the production of PAI-1 in cultured human umbilical vein endothelial cells (HUVEC). Lp(a) and Lp(a)-free, low density lipoprotein (LDL) were prepared using lysine-Sepharose 4B affinity chromatography. Incubations with 10(-8) M levels of native Lp(a) moderately increased 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 oxidative modification with copper ion. The stimulation of oxidized Lp(a) on PAI-1 production reached plateau in EC treated with 10-20 nM oxidized Lp(a) modified by microM CuSO4. Treatment with 0.2 micrograms/ml of actinomycin D significantly reduced native and oxidized Lp(a)-induced PAI-1 overproduction in EC. Increases in the steady state levels of PAI-1 mRNA were detected in native or oxidized Lp(a)-treated EC. The effect of 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 results of the present paper demonstrate that oxidative modification enhances Lp(a)-induced PAI-1 production in vascular endothelial cells at RNA transcription level, which suggests that oxidization potentially amplifies the anti-fibrinolytic and thrombotic effect of Lp(a).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Northern
  • Cells, Cultured
  • Copper Sulfate / pharmacology
  • Endothelium, Vascular / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Lipoprotein(a) / metabolism
  • Lipoprotein(a) / physiology*
  • Oxidation-Reduction
  • Plasminogen Activator Inhibitor 1 / biosynthesis*
  • Plasminogen Activator Inhibitor 1 / genetics
  • RNA, Messenger / metabolism
  • Thiobarbituric Acid Reactive Substances / analysis
  • Umbilical Veins

Substances

  • Lipoprotein(a)
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Thiobarbituric Acid Reactive Substances
  • Copper Sulfate