Objective Plasminogen activator inhibitor type-1
(PAI-1) is a physiologic inhibitor of fibrinolysis and a known determinant of cardiovascular risk
. That its expression is stimulated by insulin
in HepG2 human hepatoma cells has been shown earlier. Others have found that increased expression of PAI-1 is a risk factor for acute myocardial infarction. Pleiotropic (noncholesterol lowering) effects of statins
seem to reduce cardiovascular risk
. This study was designed to determine whether insulin
stimulation of PAI-1 expression is attenuated by statins
, and if so to explore mechanisms that are responsible for the attenuation.
PAI-1 protein in the conditioned media was assayed by western blotting, and PAI-1 mRNA expression was measured by real-time reverse transcriptase polymerase chain reactions.
(0.001–10 μmol/l) increased accumulation of PAI-1 protein in the conditioned media and PAI-1 mRNA expression in HepG2 cells. A transient transfection assay of the human PAI-1 promoter-luciferase construct demonstrated that insulin
increased PAI-1 promoter activity. Increased PAI-1 mRNA was attenuated significantly by U0126 and PD98059, specific inhibitors of mitogen-activated protein kinase. In contrast, GF109203X, an inhibitor of the protein kinase C pathway, and LY294002, an inhibitor of phosphatidylinositol 3-kinase, exerted no effects. Simvastatin (10 μmol/l), known to translocate membrane-bound sterol regulatory element-binding protein to nuclei, attenuated PAI-1 mRNA expression induced by insulin
. It did not affect baseline PAI-1 mRNA expression. Intraperitoneal injection of insulin
(0.1 IU/kg) increased concentrations of PAI-1 antigen in plasma in mice within 3 h, correlating with hepatic PAI-1 mRNA expression.
-mediated augmented expression of PAI-1 may be amenable to suppression attributable to pleiotropic effects of statins
, potentially diminishing cardiovascular risk
in patients with insulin