Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes

Abstract

Plasminogen activator inhibitor type-1 (PAI-1), an established marker and mediator of cardiovascular risk, is produced extensively in adipose tissue. Fibrates are hypolipidemic peroxisome proliferator activated receptor-alpha (PPARalpha) agonists. Recent laboratory and clinical observations indicate that they are also anti-atherosclerotic. Mechanisms responsible, however, remain to be fully understood. The present study was designed to elucidate modulation of PAI-1 expression in adipose cells by fibrates as a potential mechanism. Expression of PPARalpha was verified by PCR, immunohistochemistry, and Western blotting. In cultured preadipocytes and adipocytes gemfibrozil and fenofibrate significantly reduced PAI-1 protein expression by up to 55 +/- 5% and 34 +/- 4% under basal conditions and up to 56 +/- 6% and 31 +/- 6% under conditions of stimulation of the cells with 40 pM transforming growth factor (TGF)beta, respectively. Quantification of mRNA showed that the gemfibrozil-induced effect was at least in part regulated at the transcriptional level. Incubations with non-fibrate PPARalpha agonists showed similar reductions in PAI-1 expression. The decrease in PAI-1 expression induced by gemfibrozil was inhibited by MK886, a PPARalpha inhibitor. Furthermore, preadipocytes isolated from PPARalpha-deficient mice produced significantly more PAI-1 than those from wild-type mice upon stimulation with TGFbeta. Finally, fenofibrate reduced PAI-1 expression both in plasma and adipose tissue of hyperlipidemic mice. Our data support the view that PPARalpha activation down-regulates PAI-expression in adipose cells that may contribute in part to the reduction in cardiovascular mortality seen with fibrates in clinical trials.