Circulation, Vol 85, 1888-1893, Copyright © 1992 by American Heart Association
S Fujii and BE Sobel
BACKGROUND. Platelet-associated epidermal growth factor (EGF) and
transforming growth factor-beta (TGF-beta) can augment synthesis of
plasminogen activator inhibitor type 1 (PAI-1). Accordingly, exacerbation
of atherogenesis may accompany release of platelet- associated growth
factors (or mitogens) occurring in association with occult, repetitive
thrombosis and thrombolysis. In the Helsinki primary prevention trial,
gemfibrozil decreased coronary events but did so essentially only in
initially hypertriglyceridemic subjects. Such subjects are known to exhibit
high concentrations of PAI-1 in plasma. METHODS AND RESULTS. To determine
whether pharmacological concentrations of gemfibrozil directly affect PAI-1
synthesis, we characterized its effects on a human hepatoma cell line (Hep
G2) in vitro. Gemfibrozil decreased basal PAI-1 secretion by 43% and
attenuated the augmentation of PAI-1 synthesis over 24 hours induced by EGF
and TGF-beta by 37% and 39% without altering overall protein synthesis.
Furthermore, it blocked the EGF and TGF-beta-induced increases in PAI-1
mRNA over 6 hours by 65% and 60%. Increases in plasma PAI activity induced
by infusion of purified growth factors or by autologous platelet lysates in
rabbits were inhibited by gemfibrozil by more than 50%. CONCLUSIONS.
Beneficial effects of gemfibrozil in reducing coronary events in
hypertriglyceridemic patients may depend, in part, on potentiation of
fibrinolysis by direct diminution of synthesis of endogenous PAI-1.
ARTICLES
Direct effects of gemfibrozil on the fibrinolytic system. Diminution of synthesis of plasminogen activator inhibitor type 1
Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110.
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