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(Circulation. 1997;95:677-683.)
© 1997 American Heart Association, Inc.

Articles

Attenuation by Gemfibrozil of Expression of Plasminogen Activator Inhibitor Type 1 Induced by Insulin and its Precursors

Thomas K. Nordt, MD; Katharina Kornas, MS; Karlheinz Peter, MD; Satoshi Fujii, MD, PhD; Burton E. Sobel, MD; Wolfgang Kubler, MD; Christoph Bode, MD

the Abteilung Kardiologie, Medizinische Klinik und Poliklinik, Ruprecht-Karls-Universitat Heidelberg, Germany (T.K.N., K.K., K.P., W.K., C.B.), and Department of Medicine, University of Vermont College of Medicine, Burlington (S.F., B.E.S.).

Correspondence to Dr Thomas K. Nordt, Abteilung Kardiologie, Med. Universitatsklinik, Bergheimer Str 58, 69115 Heidelberg, Germany. E-mail thomas_nordt@krzmail.krz.uni-heidelberg.de.

Background Insulin and its precursors found in increased plasma concentrations in non–insulin-dependent diabetes mellitus (NIDDM) augment synthesis of plasminogen activator inhibitor type 1 (PAI-1) in Hep G2 cells in vitro and in rabbit liver in vivo. Reduced endogenous fibrinolysis secondary to increased PAI-1 activity may exacerbate atherogenesis. Recently, the reduction of the coronary heart disease incidence in the Helsinki Heart Study has implicated favorable modulation of endogenous fibrinolysis by gemfibrozil.

Methods and Results In Hep G2 cells, 500 (700) µmol/L gemfibrozil decreased basal secretion of PAI-1 by 26% (43%) (P=.012 and P=.021, respectively) and attenuated insulin-induced (10 nmol/L) augmentation of PAI-1 in conditioned media by 61% (109%) (P=.010) within 24 hours. Inhibition was dependent on the duration of exposure (0 to 48 hours) and on the concentration of gemfibrozil (0 to 700 µmol/L) but not on the concentration of insulin (0.1 to 100 nmol/L). Gemfibrozil attenuated the augmentation of PAI-1 secretion induced by proinsulin (>100%), by des(31,32)proinsulin (75%), and by des(64,65)proinsulin (77%) as well (10 nmol/L each). The specificity of these effects was confirmed by the unaltered levels of newly synthesized protein (metabolic labeling) and of total protein (both in conditioned media and cell lysates). Secretion of fibrinogen by Hep G2 cells was not affected by gemfibrozil. Changes in PAI-1 protein levels reflected modulation of PAI-1 gene expression as manifested by changes in levels of 3.2-kb PAI-1 mRNA (Northern blots).

Conclusions Gemfibrozil attenuated the augmentation of synthesis and secretion of PAI-1 induced by insulin and its precursors directly and specifically. Accordingly, gemfibrozil may exert favorable therapeutic effects normalizing impaired fibrinolysis in patients with hyperinsulinemia such as NIDDM.

Key Words: insulin • diabetes mellitus • fibrinolysis • atherosclerosis • coronary disease

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