INFLUENCE OF GLYCATION ON LDL-INDUCED GENERATION OF FIBRINOLYTIC REGULATORS IN VASCULAR ENDOTHELIAL-CELLS

Hyperglycemia and dyslipidemia are two biochemical markers of diabetes mellitus. Increased incidence of cardiovascular disease and impaired fibrinolytic activity have been found in diabetic subjects. Previous s tudies have demonstrated that low density lipoproteins (LDLs) stimulat e the production of plasminogen activator inhibitor-1 (PAI-I) and redu ce the generation of tissue plasminogen activator (tPA) in vascular en dothelial cells (ECs). The present study investigated the effect of gl ycated LDL on the production of PAI-I and tPA in cultured human umbili cal vein ECs (HUVECs). Glycation increased the abundance of glucitolly sine and conjugated dienes in LDL and amplified the overproduction of PAI-I and the reduction in tPA generation from HUVECs induced by LDL. The steady-state levels of PAI-I mRNA in glycated LDL-treated ECs were significantly higher than those in native LDL-heated cells. Actinomyc in D blocked the increase in PAI-I generation induced by glycated LDL, Glycated LDL did not significantly reduce the levels of IPA mRNA but attenuated de novo synthesis of tPA in ECs. Treatment with 25 mmol/L a minoguanidine, an antioxidant and inhibitor of the formation of advanc ed glycation end products, during glycation normalized glycated LDL-in duced generation of PAI-I and tPA in ECs. The results of the present s tudy indicate that glycation enhances the production of PAI-I and atte nuates tPA synthesis in ECs induced by LDL, which may contribute to th e increased incidence of cardiovascular complications in diabetes. For mation of advanced glycation end products or peroxidation may be invol ved in glycated LDL-induced alterations in the generation of fibrinoly tic regulators from ECs.