Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states.
Accelerated atherosclerosis accompanying diabetes mellitus, obesity, and some types of hypertension has been associated with hyperinsulinemia, augmented plasma plasminogen activator inhibitor type 1 (PAI-1), or both. We hypothesized that insulin and insulin-like growth factor type I (IGF-I) can influence synthesis of PAI-1, thereby potentially attenuating fibrinolysis. In HepG2 cells used as a model system, concentrations of insulin and IGF-I consistent with those seen in plasma independently stimulated PAI-1 synthesis. Accumulation of PAI-1 protein in conditioned medium over 24 hr was stimulated more with insulin alone than with the combination. Synergistic increases were evident, however, in the accumulation of PAI-1 protein over 48 hr with a concomitant increase in PAI-1 mRNA. A 10- to 20-fold increase in IGF binding protein I mRNA was seen 16-48 hr after exposure of the HepG2 cells to insulin and IGF-I, an increase abolished by cycloheximide. The results obtained are consistent with the hypothesis that hyperinsulinemia coupled with physiologic concentrations of IGF-I may attenuate fibrinolytic activity in vivo, thereby contributing to accelerated atherosclerosis.
Schneider
D J
DJ
Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110.
Sobel
B E
BE
D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms; D008545:Melanoma / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D003513:Cycloheximide