Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis.
Because of the frequent occurrence of premature cardiovascular disease in patients with non-insulin-dependent, type II diabetes mellitus (NIDDM), the attenuated fibrinolytic activity of plasma from type II diabetic patients with increased concentrations of plasminogen activator inhibitor type-1 (PAI-1), and the fact that insulin stimulates synthesis of PAI-1 by human hepatic cells in vitro, we and others have hypothesized 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 associated with type II diabetes could influence the synthesis and secretion of PAI-1 directly. The present study was performed to determine whether PAI-1 secretion is or is not sensitive to the prevailing concentration of glucose in the conditioned medium of endothelial and liver cells, 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 not increase as a function of increasing concentrations of glucose, whether or not insulin was present. In contrast, with pig aortic endothelial cells, the secretion of PAI-1 increased significantly with extracellular glucose with or without insulin. The increases in PAI-1 were specific (as shown by metabolic labeling experiments) and not attributable to osmotic effects (as shown by replacement of glucose by sorbitol).(ABSTRACT TRUNCATED AT 250 WORDS)
Nordt
T K
TK
Cardiovascular Division, Washington University School of Medicine, St Louis, Mo 63110.
Klassen
K J
KJ
Schneider
D J
DJ
Sobel
B E
BE
D000818:Animals; D001011:Aorta; D017077:Culture Media, Conditioned; D004247:DNA / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005342:Fibrinolysis / Q000502:physiology*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D004247:DNA; D005947:Glucose