Attenuation by fibrates of plasminogen activator inhibitor type-1 expression in human arterial smooth muscle cells

Human atherosclerotic lesions exhibit increased expression of plasminogen a ctivator inhibitor type-1 (PAI- 1) that has been implicated in atherogenesi s. Although vascular smooth muscle cells are a predominant source of PAI-1 expression potentially favorable modulation of PAI-1 expression by fibrates has not yet been characterized in these cells. Human aortic smooth muscle cells were exposed to selected growth factors. P AI-I expression was stimulated most powerfully by TGF-P (EC50 = 0.2 ng/ml, up to 12-fold increase). Gemfibrozil inhibited basal PAI-1 expression by 23 % (p = ns) and TGF-beta -induced PAI-1 expression by 52% (p = 0.017) wherea s t-PA and total protein synthesis was not affected. Changes in PAI-1 prote in accumulation reflected PAI-1 Gene expression attributable to modulation of half-life of PAI- I mRNA by gemfibrozil. Inhibition by other fibrates wa s less. Gemfibrozil specifically attenuates TGF-p-induced PAI-1 expression in human arterial smooth muscle cells. Thus, fibrates are promising agents for norm alizing increased PAI- I expression in arterial walls in patients in whom P AI-1 expression is increased.