The effects of glycated lipoproteins on production of fibrinolytic regulators in vascular endothelial cells

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Zhang, Jianying
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The present study investigated the effects of glycated low density lipoprot ins (LDL) and lipoprotein(a) (Lp(a)) on the production of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) from cultured human umbilical vein endothelial cells (HUVEC). The levels of PAI-1 antigen were increased in the post-cultural media of HUVEC treated with native LDL or Lp(a) for 124 h. Glycation amplified the increase in PAI-1 secretion induced by native lipoproteins from HUVEC. A significant increase in PAI-1 generation was found in cultures treated with $\ge$50 $\mu$g/ml of glycated LDL or with 5 $\mu$g/ml of glycated Lp(a) for $\ge$24 h. The level of 2.4 kb PAI-1 mRNA in HUVEC treated with glycated LDL or Lp(a) was significantly increased and that was associated with moderate reduction of 3.4 kb PAI-1 mRNA level. The de novo synthesis and secretion of t-PA in HUVEC treated with 100 $\mu$g/ml of native LDL or with 5 $\mu$g/ml of native Lp(a) were reduced by incubation for $\ge$16 h. Treatment with $\ge$25 $\mu$g/ml of native LDL or $\ge$2.5 $\mu$g/ml of native Lp(a) for 24 h significantly reduced the secretion of t-PA from HUVEC compared to control cultures. Treatments with glycated LDL or Lp(a) further reduced the secretion and de novo synthesis of t-PA from HUVEC compared to native LDL and Lp(a). Treatment with $\ge$25 mM aminoguanidine, an inhibitor of the formation for advanced glycation end products (AGEs), during the glycation of lipoproteins normalized the generation of PAI-1 and t-PA from HUVEC induced by glycated lipoproteins. The results of the present study indicate that glycation enhances the production of PAI-1 and attenuates the synthesis of t-PA in vascular endothelial cells (EC) induced by native lipoproteins. (Abstract shortened by UMI.)