Direct effects of gemfibrozil on the fibrinolytic system. Diminution of synthesis of plasminogen activator inhibitor type 1.

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.