AUGMENTATION OF SYNTHESIS OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 IN ARTERIAL ENDOTHELIAL-CELLS BY GLUCOSE AND ITS IMPLICATIONS FOR LOCALFIBRINOLYSIS

Because of the frequent occurrence of premature cardiovascular disease in patients with non-insulin-dependent, type II diabetes mellitus (NI DDM), the attenuated fibrinolytic activity of plasma from type II diab etic patients with increased concentrations of plasminogen activator i nhibitor type-1 (PAI-1), and the fact that insulin stimulates synthesi s of PAI-1 by human hepatic cells in vitro, we and others have hypothe sized that accelerated vascular disease in type II diabetes may result in part from impaired fibrinolysis secondary to excessive elaboration of PAI-1 stimulated by insulin. Alternatively, the hyperglycemia asso ciated with type II diabetes could influence the synthesis and secreti on of PAI-1 directly. The present study was performed to determine whe ther PAI-1 secretion is or is not sensitive to the prevailing concentr ation of glucose in the conditioned medium of endothelial and liver ce lls, which are thought to be the major sources of circulating PAI-1 in vivo. Confluent cells were exposed to 0, 2.8, 5.6, 11.1, or 22.2 mmol /L (0, 50, 100, 200, or 400 mg/dL) glucose in medium without serum and subsequently to media with or without insulin (7.3 nmol/L). Secretion of PAI-1 by highly differentiated human hepatoma (Hep G2) cells did n ot increase as a function of increasing concentrations of glucose, whe ther or not insulin was present. In contrast, with pig aortic endothel ial cells, the secretion of PAI-1 increased significantly with extrace llular glucose with or without insulin. The increases in PAI-1 were sp ecific (as shown by metabolic labeling experiments) and not attributab le to osmotic effects (as shown by replacement of glucose by sorbitol) . Furthermore, the changes were paralleled by a specific, significant increase in the concentration of PAI-1 mRNA. These results indicate th at increases in PAI-1 activity in type II diabetic patients are likely to be attributable to direct effects of glucose on the synthesis of P AI-1 by arterial endothelial cells, in addition to the effects of insu lin on the synthesis of PAI-1 by liver cells. The effects of glucose o n endothelial cells may contribute to reduced local fibrinolysis, ther eby exacerbating atherogenesis.