Influence of Glycation on LDL-Induced Generation of Fibrinolytic Regulators in Vascular Endothelial Cells

From the Departments of Internal Medicine and Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.

Correspondence to Dr Garry X. Shen, Departments of Internal Medicine and Physiology, University of Manitoba, BS439 730 William Ave, Winnipeg, Manitoba, Canada R3E 3J7. E-mail gshen{at}ms.umanitoba.ca

Abstract—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 studies have demonstrated that low density lipoproteins (LDLs) stimulate the production of plasminogen activator inhibitor-1 (PAI-1) and reduce the generation of tissue plasminogen activator (tPA) in vascular endothelial cells (ECs). The present study investigated the effect of glycated LDL on the production of PAI-1 and tPA in cultured human umbilical vein ECs (HUVECs). Glycation increased the abundance of glucitollysine and conjugated dienes in LDL and amplified the overproduction of PAI-1 and the reduction in tPA generation from HUVECs induced by LDL. The steady-state levels of PAI-1 mRNA in glycated LDL–treated ECs were significantly higher than those in native LDL–treated cells. Actinomycin D blocked the increase in PAI-1 generation induced by glycated LDL. Glycated LDL did not significantly reduce the levels of tPA mRNA but attenuated de novo synthesis of tPA in ECs. Treatment with 25 mmol/L aminoguanidine, an antioxidant and inhibitor of the formation of advanced glycation end products, during glycation normalized glycated LDL–induced generation of PAI-1 and tPA in ECs. The results of the present study indicate that glycation enhances the production of PAI-1 and attenuates tPA synthesis in ECs induced by LDL, which may contribute to the increased incidence of cardiovascular complications in diabetes. Formation of advanced glycation end products or peroxidation may be involved in glycated LDL–induced alterations in the generation of fibrinolytic regulators from ECs.

Key Words: glycated LDL • plasminogen activator inhibitor-1 • tissue plasminogen activator • endothelial cells • aminoguanidine

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